Phthalazine Derivatives as Inhibitors of PARP1, PARP2, and/or Tubulin Useful for the Treatment of Cancer

ABSTRACT

The application relates to phthalazine derivatives of formula (I) which are inhibitors of PARP1, PARP2 and/or tubulin and thus useful for the treatment of cancer. Also disclosed are pharmaceutical formulations containing such compounds, as well as combinations of these compounds with at least one additional therapeutic agent.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims benefit of priority to U.S. ProvisionalPatent Application No. 62/354,449, filed Jun. 24, 2016, and U.S.Provisional Patent Application No. 62/426,095 filed Nov. 23, 2016, bothof which are incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

The high proliferation rate of cancer cells is a result not only ofdecreased cell death but also of improperly regulated cell cycling,allowing evasion of growth suppressing signals. Although multiple cellcycle checkpoints can be impaired in cancer, the mitotic or spindleassembly checkpoint is of great importance both in tumorigenesis and asan anticancer target. This point of regulation, which is responsible forensuring appropriate chromosome segregation, is required for cellviability. Cells with a weakened mitotic checkpoint are capable ofsurvival but do not maintain proper chromosome segregation, resulting ingenomic instability and aneuploidy. PARP (poly(ADP-ribose) polymerase)is an important protein in DNA repair pathways especially the baseexcision repair (BER). BER is involved in DNA repair of single strandbreaks (SSBs). If BER is impaired, inhibiting PARP, SSBs accumulate andbecome double stand breaks (DSBs). In addition, PARP can act on manymediators of cell cycle progression through its effects on geneexpression. However, direct regulation of the mitotic checkpoint by PARPis another important factor that may be exploited in the development ofan optimal cancer therapy.

Recent reports suggest multiple roles for PARP in the structuralmachinery of mitosis. First, PAR, which is primarily synthesized byPARP, is required for assembly and function of the bipolar spindle. Inaddition, PARP-1 both localizes to and PARylates proteins at centromeresand centrosomes during mitosis. PARP-1 also mediates PARylation of p53,which is responsible for regulating centrosome duplication andmonitoring chromosomal stability. Loss of PARP activity is associatedwith mislocalization of centromeric and centrosomal proteins, resultingin incomplete synapsis of homologous chromosomes, defective chromatinmodifications, and failure to maintain metaphase arrest, indicating lossof mitotic checkpoint integrity. Similarly, inhibition of PARP-1 isassociated with genomic instability characterized by reduced stringencyof mitotic checkpoints, centrosome hyper-amplification, and chromosomalaneuploidy. Furthermore, PARP-1 has been shown to interact with the E3ubiquitin ligase, CHFR, a tumor suppressor with an important role in theearly mitotic checkpoint. Binding of these two proteins results in cellcycle arrest in prophase, an effect stimulated by microtubule inhibitorsresulting in resistance to this class of drugs in cancer cells. Thus,inhibition of PARP or microtubules, or both, could significantlyincrease cancer cells death, and may be a promising anti-cancerstrategy.

The present invention relates to compounds having microtubule-perturbingand/or anti-PARP activity. These compounds may be used for treatment inthe animal of a disease associated with tubulin polymerization or PARP,or both. This, and other uses of these compounds are described herein.

SUMMARY OF THE INVENTION

This invention provides, among other things, compounds useful fortreating diseases associated with PARP1 (Poly ADP Ribose Polymerase1)and/or PARP2 (Poly ADP Ribose Polymerase2) and/or tubulin,pharmaceutical formulations containing such compounds, as well ascombinations of these compounds with at least one additional therapeuticagent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A-FIG. 1O provides biological data for compounds of the invention.For the Trapped PARP-DNA column, TC=Induces Trapped PARP-DNA complexformation in cells, NT=Not Tested.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions and Abbreviations

As used herein, the singular forms “a,” “an”, and “the” include pluralreferences unless the context clearly dictates otherwise. For example,reference to “an active agent” includes a single active agent as well astwo or more different active agents in combination. It is to beunderstood that present teaching is not limited to the specific dosageforms, carriers, or the like, disclosed herein and as such may vary.

The abbreviations used herein generally have their conventional meaningwithin the chemical and biological arts.

The following abbreviations have been used: Ac is acetyl; AcOH is aceticacid; ACTBr is cetyltrimethylammonium bromide; AIBN isazobisisobutyronitrile or 2,2 azobisisobutyronitrile; aq. is aqueous; Aris aryl; B₂pin₂ is bis(pinacolato)diboron; Bn is, in general, benzyl[see Cbz for one example of an exception]; (BnS)₂ is benzyl disulfide;BnSH is benzyl thiol or benzyl mercaptan; BnBr is benzyl bromide; Boc istert-butoxy carbonyl; Boc₂O is di-tert-butyl dicarbonate; Bz is, ingeneral, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z isbenzyloxycarbonyl or carboxybenzyl; Cs₂CO₃ is cesium carbonate; CSA iscamphor sulfonic acid; CTAB is cetyltrimethylammonium bromide; Cy iscyclohexyl; DABCO is 1,4-diazabicyclo[2.2.2]octane; DCM isdichloromethane or methylene chloride; DHP is dihydropyran; DIAD isdiisopropyl azodicarboxylate; DIEA or DIPEA isN,N-diisopropylethylamine; DMAP is 4-(dimethylamino)pyridine; DME is1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO isdimethylsulfoxide; equiv or eq. is equivalent; EtOAc is ethyl acetate;EtOH is ethanol; Et₂O is diethyl ether; EDCI isN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride; ELS isevaporative light scattering; equiv or eq is equivalent; h is hours;HATU is O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HOBt is N-hydroxybenzotriazole; HCl is hydrochloricacid; HPLC is high pressure liquid chromatography; ISCO Companion isautomated flash chromatography equipment with fraction analysis by UVabsorption available from Presearch; KOAc or AcOK is potassium acetate;K₂CO₃ is potassium carbonate; LiAlH₄ or LAH is lithium aluminum hydride;LDA is lithium diisopropylamide; LHMDS is lithium bis(trimethylsilyl)amide; KHMDS is potassium bis(trimethylsilyl) amide; LiOH is lithiumhydroxide; m-CPBA is 3-chloroperoxybenzoic acid; MeCN or ACN is methylcyanide or cyanomethane or ethanenitrile or acetonitrile which are allnames for the same compound; MeOH is methanol; MgSO₄ is magnesiumsulfate; mins or min is minutes; Mp or MP is melting point; NaCNBH₃ issodium cyanoborohydride; NaOH is sodium hydroxide; Na₂SO₄ is sodiumsulfate; NBS is N-bromosuccinimide; NH₄Cl is ammonium chloride; NIS isN-iodosuccinimide; N₂ is nitrogen; NMM is N-methylmorpholine; n-BuLi isn-butyllithium; overnight is O/N; PdCl₂(pddf) is1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd/C is thecatalyst known as palladium on carbon; Pd₂(dba)₃ is an organometalliccatalyst known as tris(dibenzylideneacetone) dipalladium(0); Ra Ni orRaney Ni is Raney nickel; Ph is phenyl; PMB is p-methoxybenzyl; PrOH is1-propanol; iPrOH is 2-propanol; POCl₃ is phosphorus chloride oxide;PTSA is para-toluene sulfonic acid; Pyr. or Pyr or Py as used hereinmeans pyridine; RT or rt or r.t. is room temperature; sat. is saturated;Si-amine or Si—NH₂ is amino-functionalized silica, available fromSiliCycle; Si-pyr is pyridyl-functionalized silica, available fromSiliCycle; TEA or Et₃N is triethylamine; TFA is trifluoroacetic acid;Tf₂O is trifluoromethanesulfonic anhydride; THF is tetrahydrofuran; TFAAis trifluoroacetic anhydride; THP is tetrahydropyranyl; TMSI istrimethylsilyl iodide; H₂O is water; diNO₂PhSO₂Cl is dinitrophenylsulfonyl chloride; 3-F-4-NO₂—PhSO₂Cl is 3-fluoro-4-nitrophenylsulfonylchloride; 2-MeO-4-NO₂—PhSO₂Cl is 2-methoxy-4-nitrophenylsulfonylchloride; and (EtO)₂POCH₂COOEt is a triethylester of phosphonoaceticacid known as triethyl phosphonoacetate.

“Compound of the invention,” as used herein refers to the compoundsdiscussed herein, salts (e.g. pharmaceutically acceptable salts),prodrugs, solvates and hydrates of these compounds.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents, which would result from writing thestructure from right to left, e.g., —CH₂O— is intended to also recite—OCH₂—.

The term “poly” as used herein means at least 2. For example, apolyvalent metal ion is a metal ion having a valency of at least 2.

“Moiety” refers to a radical of a molecule that is attached to theremainder of the molecule.

The symbol

, whether utilized as a bond or displayed perpendicular to a bond,indicates the point at which the displayed moiety is attached to theremainder of the molecule.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). In some embodiments, the term “alkyl” means astraight or branched chain, or combinations thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals. Examples of saturated hydrocarbon radicals include, but arenot limited to, groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, cyclobutyl, cyclohexyl,(cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, homologs and isomersof, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingeight or fewer carbon atoms.

The term “alkenylene” by itself or as part of another substituent meansa divalent radical derived from an alkene.

The term “cycloalkylene” by itself or as part of another substituentmeans a divalent radical derived from a cycloalkane.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical derived from an heteroalkane.

The term “heterocycloalkylene” by itself or as part of anothersubstituent means a divalent radical derived from an heterocycloalkane.

The term “arylene” by itself or as part of another substituent means adivalent radical derived from an aryl.

The term “heteroarylene” by itself or as part of another substituentmeans a divalent radical derived from heteroaryl.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom. In someembodiments, the term “heteroalkyl,” by itself or in combination withanother term, means a stable straight or branched chain, or combinationsthereof, consisting of the stated number of carbon atoms and at leastone heteroatom. In an exemplary embodiment, the heteroatoms can beselected from the group consisting of B, O, N and S, and wherein thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenheteroatom may optionally be quaternized. The heteroatom(s) B, O, N andS may be placed at any interior position of the heteroalkyl group or atthe position at which the alkyl group is attached to the remainder ofthe molecule. Examples include, but are not limited to, —O—CH₃,—CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃.Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃. Similarly, the term “heteroalkylene” by itself or as partof another substituent means a divalent radical derived fromheteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini (e.g., alkyleneoxy,alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Stillfurther, for alkylene and heteroalkylene linking groups, no orientationof the linking group is implied by the direction in which the formula ofthe linking group is written. For example, the formula —C(O)₂R′—represents both —C(O)₂R′— and —R′C(O)₂—.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,2-(4-methylpiperazin-1-yl)ethyl, 3-(4-methylpiperazin-1-yl)propyl,2-morpholinoethyl, 3-morpholinopropyl, 1-methylazetidin-3-yl,1-ethylazetidin-3-yl, 1-isopropylazetidin-3-yl, 1-methylpiperidin-4-yl,1-ethylpiperidin-4-yl or, 1-isopropylpiperidin-4-yl,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl,2,2-difluoroethyl,2-chloroethyl, 3-chloropropyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 or 2 or 3 rings), which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms. In an exemplary embodiment, theheteroatom is selected from B, N, O, and S, wherein the nitrogen andsulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. A heteroaryl group can be attached to theremainder of the molecule through a heteroatom. Non-limiting examples ofaryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″,—SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR′″″—C(NR′R″R′″)═NR″″, —NR″″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR″SO₂R′, —CN, —NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, andfluoro(C₁-C₄)alkyl, in a number ranging from zero to (2m′+1), where m′is the total number of carbon atoms in such radical. R′, R″, R′″, R″″and R′″″ each preferably independently refer to hydrogen, substituted orunsubstituted haloalkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, e.g., aryl substituted with 1-3 halogens,substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, orarylalkyl groups. When a compound of the invention includes more thanone R group, for example, each of the R groups is independently selectedas are each R′, R″, R′″, R″″ and R′″″ groups when more than one of thesegroups is present. When R′ and R″ are attached to the same nitrogenatom, they can be combined with the nitrogen atom to form a 5-, 6-, or7-membered ring. For example, —NR′R″ is meant to include, but not belimited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussionof substituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR′″″—C(NR′ R″R′″)═NR″″,—NR″″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR″SO₂R′, —CN,—NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in anumber ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R′″, R″″ and R′″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,R″″ and R′″″ groups when more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″ and R′″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅or C₆ alkyl.

“Ring” as used herein, means a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. A ringincludes fused ring moieties. The number of atoms in a ring is typicallydefined by the number of members in the ring. For example, a “5- to7-membered ring” means there are 5 or 6 or 7 atoms in the encirclingarrangement. Unless otherwise specified, the ring optionally includes aheteroatom. Thus, the term “5 to 7-membered ring” or “5 or 6 or 7membered ring” includes, for example phenyl, pyridinyl and piperidinyl.The term “5 to 7-membered heterocycloalkyl ring” “5 or 6 or 7-memberedheterocycloalkyl ring”, on the other hand, would include pyridinyl andpiperidinyl, but not phenyl. The term “ring” further includes a ringsystem comprising more than one “ring”, wherein each “ring” isindependently defined as above.

As used herein, the term “heteroatom” includes atoms other than carbon(C) and hydrogen (H). Examples include oxygen (O), nitrogen (N) sulfur(S), silicon (Si), germanium (Ge), and aluminum (Al).

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include triflate, chloro, bromoand iodo groups; sulfonic ester groups, such as mesylate, tosylate,brosylate, nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The symbol “R” is a general abbreviation that represents a substituentgroup that is selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted cycloalkyl and substituted or unsubstitutedheterocycloalkyl groups.

By “effective” amount of a drug, formulation, or permeant is meant asufficient amount of an active agent to provide the desired local orsystemic effect. A “Topically effective,” “pharmaceutically effective,”or “therapeutically effective” amount refers to the amount of drugneeded to effect the desired therapeutic result.

The term “pharmaceutically acceptable salt” is meant to include a saltof a compound of the invention which is prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino (suchas choline or diethylamine or amino acids such as d-arginine,1-arginine, d-lysine, or 1-lysine), or magnesium salt, or a similarsalt. When compounds of the invention contain relatively basicfunctionalities, acid addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, for example, Bergeet al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain bothbasic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompounds in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the invention provides compounds which are ina prodrug form. Prodrugs of the compounds described herein readilyundergo chemical changes under physiological conditions to provide thecompounds of the invention. Additionally, prodrugs can be converted tothe compounds of the invention by chemical or biochemical methods in anex vivo environment.

Certain compounds of the invention can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the invention. Certain compounds of the invention may exist inmultiple crystalline or amorphous forms.

Certain compounds of the invention possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the invention. The graphic representations of racemic,ambiscalemic and scalemic or enantiomerically pure compounds used hereinare taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and brokenwedges are used to denote the absolute configuration of a stereocenterunless otherwise noted. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms areincluded.

Compounds of the invention can exist in particular geometric orstereoisomeric forms. The invention contemplates all such compounds,including cis- and trans-isomers, (−)- and (+)-enantiomers, (R)- and(S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, such as enantiomericallyor diastereomerically enriched mixtures, as falling within the scope ofthe invention. Additional asymmetric carbon atoms can be present in asubstituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this invention.

Optically active (R)- and (S)-isomers and d and l isomers can beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If, for instance, a particular enantiomer of acompound of the invention is desired, it can be prepared by asymmetricsynthesis, or by derivatization with a chiral auxiliary, where theresulting diastereomeric mixture is separated and the auxiliary groupcleaved to provide the pure desired enantiomers. Alternatively, wherethe molecule contains a basic functional group, such as an amino group,or an acidic functional group, such as a carboxyl group, diastereomericsalts can be formed with an appropriate optically active acid or base,followed by resolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means known in the art, andsubsequent recovery of the pure enantiomers. In addition, separation ofenantiomers and diastereomers is frequently accomplished usingchromatography employing chiral, stationary phases, optionally incombination with chemical derivatization (e.g., formation of carbamatesfrom amines).

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe invention, whether radioactive or not, are intended to beencompassed within the scope of the invention.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable vehicle” refers to any formulation or carrier medium thatprovides the appropriate delivery of an effective amount of an activeagent as defined herein, does not interfere with the effectiveness ofthe biological activity of the active agent, and that is sufficientlynon-toxic to the host or patient. Representative carriers include water,oils, both vegetable and mineral, cream bases, lotion bases, ointmentbases and the like. These bases include suspending agents, thickeners,penetration enhancers, and the like. Their formulation is well known tothose in the art of cosmetics and topical pharmaceuticals. Additionalinformation concerning carriers can be found in Remington: The Scienceand Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins(2005) which is incorporated herein by reference.

The term “pharmaceutically acceptable additive” refers to preservatives,antioxidants, fragrances, emulsifiers, dyes and excipients known or usedin the field of drug formulation and that do not unduly interfere withthe effectiveness of the biological activity of the active agent, andthat is sufficiently non-toxic to the host or patient. Additives fortopical formulations are well-known in the art, and may be added to thetopical composition, as long as they are pharmaceutically acceptable andnot deleterious to the epithelial cells or their function. Further, theyshould not cause deterioration in the stability of the composition. Forexample, inert fillers, anti-irritants, tackifiers, excipients,fragrances, opacifiers, antioxidants, gelling agents, stabilizers,surfactant, emollients, coloring agents, preservatives, bufferingagents, other permeation enhancers, and other conventional components oftopical or transdermal delivery formulations as are known in the art.

The term “excipients” is conventionally known to mean carriers, diluentsand/or vehicles used in formulating drug compositions effective for thedesired use.

The terms “effective amount” or a “therapeutically effective amount” ofa drug or pharmacologically active agent refers to a nontoxic butsufficient amount of the drug or agent to provide the desired effect. Inthe oral dosage forms of the present disclosure, an “effective amount”of one active of the combination is the amount of that active that iseffective to provide the desired effect when used in combination withthe other active of the combination. The amount that is “effective” willvary from subject to subject, depending on the age and general conditionof the individual, the particular active agent or agents, and theappropriate “effective” amount in any individual case may be determinedby one of ordinary skill in the art using routine experimentation.

The phrases “active ingredient”, “therapeutic agent”, “active”, or“active agent” mean a chemical entity which can be effective in treatinga targeted disorder, disease or condition.

The phrase “pharmaceutically acceptable” means moieties or compoundsthat are, within the scope of medical judgment, suitable for use inhumans without causing undesirable biological effects such as unduetoxicity, irritation, allergic response, and the like, for example.

The phrase “oral dosage form” means any pharmaceutical formulationadministered to a subject via the oral cavity. Exemplary oral dosageforms include tablets, capsules, films, powders, sachets, granules,solutions, solids, suspensions or as more than one distinct unit (e.g.,granules, tablets, and/or capsules containing different actives)packaged together for co-administration, and other formulations known inthe art. An oral dosage form can be one, two, three, four, five or sixunits. When the oral dosage form has multiple units, all of the unitsare contained within a single package, (e.g. a bottle or other form ofpackaging such as a blister pack). When the oral dosage form is a singleunit, it may or may not be in a single package. In a preferredembodiment, the oral dosage form is one, two or three units. In aparticularly preferred embodiment, the oral dosage form is one unit.

The phrase “unit”, as used herein, refers to the number of discreteobjects to be administered which comprise the dosage form. In someembodiments, the dosage form includes a compound of the invention in onecapsule. This is a single unit. In some embodiments, the dosage formincludes a compound of the invention as part of a therapeuticallyeffective dosage of a cream or ointment. This is also a single unit. Insome embodiments, the dosage form includes a compound of the inventionand another active ingredient contained within one capsule, or as partof a therapeutically effective dosage of a cream or ointment. This is asingle unit, whether or not the interior of the capsule includesmultiple discrete granules of the active ingredient. In someembodiments, the dosage form includes a compound of the invention in onecapsule, and the active ingredient in a second capsule. This is a twounit dosage form, such as two capsules or tablets, and so such units arecontained in a single package. Thus the term ‘unit’ refers to the objectwhich is administered to the animal, not to the interior components ofthe object.

“Biological medium,” as used herein refers to both in vitro and in vivobiological milieus. Exemplary in vitro “biological media” include, butare not limited to, cell culture, tissue culture, homogenates, plasmaand blood. In vivo applications are generally performed in mammals,preferably humans.

“Inhibiting” and “blocking,” are used interchangeably herein to refer tothe partial or full blockade of an enzyme, such as PARP1 (Poly ADPRibose Polymerase1) and/or PARP2 and/or tubulin.

Embodiments of the invention also encompass compounds that are poly- ormulti-valent species, including, for example, species such as dimers,trimers, tetramers and higher homologs of the compounds of use in theinvention or reactive analogues thereof.

II. Introduction

The invention provides novel compounds. The novel compounds, as well aspharmaceutical formulations containing such compounds or combinations ofthese compounds with at least one additional therapeutic agent, can beused for, among other things, treating diseases, including cancer.

III. The Compounds III.a)

In one aspect, the invention provides a compound of the invention. In anexemplary embodiment, the invention is a compound described herein. Inan exemplary embodiment, the invention is a compound according to aformula described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(I):

wherein T has a structure which is

wherein

presents a covalent bond to the methylene group in formula (I) and

represents a covalent bond to the U ring in formula (I)wherein formula (C)

wherein

represents a covalent bond to the T ring in formula (I) and

represents a covalent bond to —NH—Y—Z—R¹ in formula (I), has a structurewhich is

wherein Y is C(O) or S(O)₂; Z is —O— or —CH₂— or —NH— or —N(CH₂R⁷)—wherein R⁷ is hydrogen or substituted or unsubstituted C₁ or C₂ or C₃ orC₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl; R¹ is hydrogen orsubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ orC₈ or C₉ or C₁₀ alkyl or substituted or unsubstituted C₁ or C₂ or C₃ orC₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ heteroalkyl or substituted orunsubstituted aryl or substituted or unsubstituted arylalkyl orsubstituted or unsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl; R² is hydrogen or halogen or substituted orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl; R³ is hydrogen or halogen or substituted or unsubstituted C₁ orC₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl or substitutedor unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ orC₁₀ alkoxy; R⁴ is hydrogen or halogen or substituted or unsubstituted C₁or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl orsubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ orC₈ or C₉ or C₁₀ alkoxy; R⁵ is hydrogen or halogen or substituted orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl; and R⁶ is hydrogen or halogen or substituted or unsubstituted C₁or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(Ia):

wherein T has a structure which is

wherein

represents a covalent bond to the methylene group in formula (Ia) and

represents a covalent bond to the U ring in formula (Ia)wherein formula (C1)

wherein

represents a covalent bond to the T ring in formula (Ia), has astructure which is

wherein R² is hydrogen or halogen or substituted or unsubstituted C₁ orC₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl; R³ ishydrogen or halogen or substituted or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl or substituted orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkoxy; R⁴ is hydrogen or halogen or substituted or unsubstituted C₁ orC₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl or substitutedor unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ orC₁₀ alkoxy; R⁵ is hydrogen or halogen or substituted or unsubstituted C₁or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl; and R⁶ ishydrogen or halogen or substituted or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl.

In an exemplary embodiment, according to formula (I), Z, R¹, R², R³, R⁴,R⁵, and R⁶ are as described herein, Y is C(O). In an exemplaryembodiment, according to formula (I), Z, R¹, R², R³, R⁴, R⁵, and R⁶ areas described herein, Y is S(O)₂. In an exemplary embodiment, accordingto formula (I), Y, R¹, R², R³, R⁴, R⁵, and R⁶ are as described herein, Zis —O—. In an exemplary embodiment, according to formula (I), Y, R¹, R²,R³, R⁴, R⁵, and R⁶ are as described herein, Z is —CH₂—. In an exemplaryembodiment, according to formula (I), Y, R¹, R², R³, R⁴, R⁵, and R⁶ areas described herein, Z is —NH—. In an exemplary embodiment, according toformula (I), Y, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as described herein,Z is —N(CH₂R⁷)—.

In an exemplary embodiment, according to formula (I), R¹, R², R³, R⁴ andR⁷ are as described herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—,R⁵ is halogen, and R⁶ is halogen. In an exemplary embodiment, accordingto formula (I), R¹, R², R³, R⁴ and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R⁵ is halogen, and R⁶ is fluorineor chlorine. In an exemplary embodiment, according to formula (I), R¹,R², R³, R⁴ and R⁷ are as described herein, Y is C(O), Z is —O— or —NH—or —N(CH₂R⁷)—, Y is C(O), Z is —O—, R⁵ is hydrogen, and R⁶ is halogen orunsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl. In an exemplary embodiment, according to formula (I), R¹, R², R³,R⁴ and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, R⁶ is hydrogen, and R⁵ is halogen or unsubstituted C₁ or C₂or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl.

In an exemplary embodiment, according to formula (I), R¹, R², and R⁷ areas described herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R³ ishydrogen or halogen or unsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ orC₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇or C₈ or C₉ or C₁₀ alkyl, R⁴ is hydrogen or halogen or C₁ or C₂ or C₃alkoxy, R⁵ is hydrogen or halogen or unsubstituted C₁ or C₂ or C₃haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl, and R⁶ is hydrogen orhalogen or unsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ orC₉ or C₁₀ alkyl. In an exemplary embodiment, according to formula (I),R¹, R², and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, R³ is hydrogen or halogen or unsubstituted C₁ or C₂ or C₃haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl, R⁴ is hydrogen or halogen orC₁ or C₂ or C₃ alkoxy, R⁵ is hydrogen or halogen or unsubstituted C₁ orC₂ or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ orC₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl, and R⁶ is hydrogenor halogen. In an exemplary embodiment, according to formula (I), R¹,R², and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, R³ is hydrogen or halogen or unsubstituted C₁ or C₂ or C₃haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl, R⁴ is hydrogen or halogen orC₁ or C₂ or C₃ alkoxy, R⁵ is hydrogen or halogen, and R⁶ is hydrogen orhalogen or unsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ orC₉ or C₁₀ alkyl. In an exemplary embodiment, according to formula (I),R¹, R², and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, R³ is halogen, and R⁴ is fluorine or chlorine, R⁵ ishydrogen or halogen, and R⁶ is hydrogen or halogen. In an exemplaryembodiment, according to formula (I), R¹, R², and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R³ is unsubstitutedC₁ or C₂ or C₃ or heteroalkyl, and R⁴ is fluorine or chlorine, R⁵ ishydrogen or halogen, and R⁶ is hydrogen or halogen. In an exemplaryembodiment, according to formula (I), R¹, R², and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, Y is C(O), Z is —O—,R³ is hydrogen or halogen or unsubstituted C₁ or C₂ or C₃ haloalkyl orC₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆or C₇ or C₈ or C₉ or C₁₀ alkyl, R⁴ is C₁ or C₂ or C₃ alkoxy, R⁵ ishydrogen or halogen, and R⁶ is hydrogen or halogen. In an exemplaryembodiment, according to formula (I), R¹, R², and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R³ is hydrogen orhalogen or unsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ orC₉ or C₁₀ alkyl, R⁴ is hydrogen, R⁵ is hydrogen or halogen, and R⁶ ishydrogen or halogen. In an exemplary embodiment, according to formula(I), R¹, R², and R⁷ are as described herein, Y is C(O), Z is —O— or —NH—or —N(CH₂R⁷)—, R³ is hydrogen, R⁴ is hydrogen or halogen or C₁ or C₂ orC₃ alkoxy, R⁵ is hydrogen or halogen, and R⁶ is hydrogen or halogen. Inan exemplary embodiment, according to formula (I), R¹, R², and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R³ isfluorine, R⁴ is hydrogen or halogen or C₁ or C₂ or C₃ alkoxy, R⁵ ishydrogen or halogen, and R⁶ is hydrogen or halogen. In an exemplaryembodiment, according to formula (I), R¹, R², and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R³ is hydrogen orhalogen or unsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ orC₉ or C₁₀ alkyl, R⁴ is hydrogen or halogen or C₁ or C₂ or C₃ alkoxy, R⁵is hydrogen or halogen, and R⁶ is fluorine or chlorine. In an exemplaryembodiment, according to formula (I), R¹, R², and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R³ is hydrogen orhalogen or unsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ orC₉ or C₁₀ alkyl, R⁴ is hydrogen or halogen or C₁ or C₂ or C₃ alkoxy, R⁵is hydrogen or halogen, and R⁶ is fluorine or chlorine. In an exemplaryembodiment, according to formula (I), R¹, R², and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R³ is fluorine, R⁴ ishydrogen or halogen or C₁ or C₂ or C₃ alkoxy, R⁵ is hydrogen, and R⁶ ishydrogen.

In an exemplary embodiment, according to formula (I), R¹ and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R² ishydrogen or halogen or substituted or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl, R³ is hydrogen or halogen orunsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl, R⁴ is hydrogen or halogen or C₁ or C₂ or C₃ alkoxy, R⁵ ishydrogen or halogen or unsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ orC₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇or C₈ or C₉ or C₁₀ alkyl, and R⁶ is hydrogen or halogen or unsubstitutedC₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ orC₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In anexemplary embodiment, according to formula (I), R¹ and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R² ishydrogen or halogen or substituted or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl, R³ is hydrogen or halogen orunsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl, R⁴ is hydrogen or halogen or C₁ or C₂ or C₃ alkoxy, R⁵ ishydrogen or halogen or unsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ orC₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇or C₈ or C₉ or C₁₀ alkyl, and R⁶ is hydrogen or halogen. In an exemplaryembodiment, according to formula (I), R¹ and R⁷ are as described herein,Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R² is hydrogen or halogen orsubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ orC₈ or C₉ or C₁₀ alkyl, R³ is hydrogen or halogen or unsubstituted C₁ orC₂ or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ orC₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl, R⁴ is hydrogen orhalogen or C₁ or C₂ or C₃ alkoxy, R⁵ is hydrogen or halogen, and R⁶ ishydrogen or halogen or unsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ orC₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇or C₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment, according toformula (I), R¹ and R⁷ are as described herein, Y is C(O), Z is —O— or—NH— or —N(CH₂R⁷)—, R² is halogen, R³ is halogen, R⁴ is fluorine orchlorine, R⁵ is hydrogen or halogen, and R⁶ is hydrogen or halogen. Inan exemplary embodiment, according to formula (I), R¹ and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R² ishydrogen, R³ is halogen, R⁴ is fluorine or chlorine, R⁵ is hydrogen orhalogen, and R⁶ is hydrogen or halogen. In an exemplary embodiment,according to formula (I), R¹ and R⁷ are as described herein, Y is C(O),Z is —O— or —NH— or —N(CH₂R⁷)—, R² is hydrogen, R³ is unsubstituted C₁or C₂ or C₃ or heteroalkyl, R⁴ is fluorine or chlorine, R⁵ is hydrogenor halogen, and R⁶ is hydrogen or halogen. In an exemplary embodiment,according to formula (I), R¹ and R⁷ are as described herein, Y is C(O),Z is —O— or —NH— or —N(CH₂R⁷)—, R² is hydrogen, R³ is hydrogen orhalogen or unsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ orC₉ or C₁₀ alkyl, R⁴ is C₁ or C₂ or C₃ alkoxy, R⁵ is hydrogen or halogen,and R⁶ is hydrogen or halogen. In an exemplary embodiment, according toformula (I), R¹ and R⁷ are as described herein, Y is C(O), Z is —O— or—NH— or —N(CH₂R⁷)—, R² is hydrogen, R³ is hydrogen or halogen orunsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl, R⁴ is hydrogen, R⁵ is hydrogen or halogen, and R⁶ is hydrogen orhalogen. In an exemplary embodiment, according to formula (I), R¹ and R⁷are as described herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R²is hydrogen, R³ is hydrogen, R⁴ is hydrogen or halogen or C₁ or C₂ or C₃alkoxy, R⁵ is hydrogen or halogen, and R⁶ is hydrogen or halogen. In anexemplary embodiment, according to formula (I), R¹ and R are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R)—, R² ishydrogen, R³ is fluorine, R⁴ is hydrogen or halogen or C₁ or C₂ or C₃alkoxy, R⁵ is hydrogen or halogen, and R⁶ is hydrogen or halogen. In anexemplary embodiment, according to formula (I), R¹ and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R′)—, R² ishydrogen, R³ is hydrogen or halogen or unsubstituted C₁ or C₂ or C₃haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl, R⁴ is hydrogen or halogen orC₁ or C₂ or C₃ alkoxy, R⁵ is hydrogen or halogen, and R⁶ is fluorine orchlorine. In an exemplary embodiment, according to formula (I), R¹ andR⁷ are as described herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R)—, R²is hydrogen, R³ is hydrogen or halogen or unsubstituted C₁ or C₂ or C₃haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl, R⁴ is hydrogen or halogen orC₁ or C₂ or C₃ alkoxy, R⁵ is hydrogen or halogen, and R⁶ is fluorine orchlorine. In an exemplary embodiment, according to formula (I), R¹ andR⁷ are as described herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R′)—,R² is methyl, R³ is hydrogen or halogen or unsubstituted C₁ or C₂ or C₃haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl, R⁴ is hydrogen or halogen orC₁ or C₂ or C₃ alkoxy, R⁵ is hydrogen or halogen, and R⁶ is fluorine orchlorine. In an exemplary embodiment, according to formula (I), R¹ andR⁷ are as described herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R′)—,R² is fluorine or chlorine, R³ is hydrogen or halogen or unsubstitutedC₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ orC₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl, R⁴ ishydrogen or halogen or C₁ or C₂ or C₃ alkoxy, R⁵ is hydrogen or halogen,and R⁶ is fluorine or chlorine. In an exemplary embodiment, according toformula (I), R¹ and R⁷ are as described herein, Y is C(O), Z is —O— or—NH— or —N(CH₂R′)—, R² is hydrogen, R³ is fluorine, R⁴ is hydrogen orhalogen or C₁ or C₂ or C₃ alkoxy, R⁵ is hydrogen, and R⁶ is hydrogen. Inan exemplary embodiment, according to formula (I), R¹ and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R² ishydrogen, R³ is fluorine, R⁴ is hydrogen, R⁵ is hydrogen, and R⁶ ishydrogen.

In an exemplary embodiment, according to formula (I), R¹, R³, R⁴, R⁵,R⁶, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R² is substituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇or C₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment, according toformula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R² is unsubstituted C₁ or C₂or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplaryembodiment, according to formula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R² isCH₃. In an exemplary embodiment, according to formula (I), R¹, R³, R⁴,R⁵, R⁶, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R² is H. In an exemplary embodiment, according toformula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R² is halogen. In an exemplaryembodiment, according to formula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R² isfluorine or chlorine. In an exemplary embodiment, according to formula(I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are as described herein, Y is C(O), Z is—O— or —NH— or —N(CH₂R⁷)—, and R² is chlorine.

In an exemplary embodiment, according to formula (I), R¹, R³, R⁴, R⁵,R⁶, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R³ is hydrogen or halogen or substituted orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₅ or C₉ or C₁₀haloalkyl or substituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ orC₆ or C₇ or C₈ or C₉ or C₁₀ heteroalkyl. In an exemplary embodiment,according to formula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R³ is substitutedC₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In anexemplary embodiment, according to formula (I), R¹, R³, R⁴, R⁵, R⁶, andR⁷ are as described herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—,and R³ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ orC₉ or C₁₀ alkyl. In an exemplary embodiment, according to formula (I),R¹, R³, R⁴, R⁵, R⁶, and R⁷ are as described herein, Y is C(O), Z is —O—or —NH— or —N(CH₂R⁷)—, and R³ is CH₃. In an exemplary embodiment,according to formula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R³ is C₁-C₄ alkylsubstituted with one or more halogen. In an exemplary embodiment,according to formula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R³ is —CF₃. In anexemplary embodiment, according to formula (I), R¹, R³, R⁴, R⁵, R⁶, andR⁷ are as described herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—,and R³ is C₁ or C₂ or C₃ alkoxy. In an exemplary embodiment, accordingto formula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R³ is —OCH₃. In an exemplaryembodiment, according to formula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R³ isC₁ or C₂ or C₃ haloalkyl. In an exemplary embodiment, according toformula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R³ is CF₃. In an exemplaryembodiment, according to formula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R³ isH. In an exemplary embodiment, according to formula (I), R¹, R³, R⁴, R⁵,R⁶, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R)—, and R³ is halogen. In an exemplary embodiment, according toformula (I), R¹, R³, R⁴, R⁵, R⁶, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R³ is fluorine or chlorine. Inan exemplary embodiment, according to formula (I), R¹, R³, R⁴, R⁵, R⁶,and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R³ is fluorine.

In an exemplary embodiment, according to formula (I), R¹, R², R³, R⁵,R⁶, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R⁴ is hydrogen or halogen or substituted orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀haloalkyl or substituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ orC₆ or C₇ or C₈ or C₉ or C₁₀ heteroalkyl. In an exemplary embodiment,according to formula (I), R¹, R², R³, R⁵, R⁶, and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁴ is halogen. Inan exemplary embodiment, according to formula (I), R¹, R², R³, R⁵, R⁶,and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R⁴ is fluorine or chlorine. In an exemplary embodiment,according to formula (I), R¹, R², R³, R⁵, R⁶, and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁴ is substitutedC₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In anexemplary embodiment, according to formula (I), R¹, R², R³, R⁵, R⁶, andR⁷ are as described herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—,and R⁴ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ orC₉ or C₁₀ alkyl. In an exemplary embodiment, according to formula (I),R¹, R², R³, R⁵, R⁶, and R⁷ are as described herein, Y is C(O), Z is —O—or —NH— or —N(CH₂R⁷)—, and R⁴ is CH₃. In an exemplary embodiment,according to formula (I), R¹, R², R³, R⁵, R⁶, and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁴ isunsubstituted C₁ or C₂ or C₃ or heteroalkyl. In an exemplary embodiment,according to formula (I), R¹, R², R³, R⁵, R⁶, and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁴ is C₁ or C₂ orC₃ alkoxy. In an exemplary embodiment, according to formula (I), R¹, R²,R³, R⁵, R⁶, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH—or —N(CH₂R⁷)—, and R⁴ is —OCH₃. In an exemplary embodiment, according toformula (I), R¹, R², R³, R⁵, R⁶, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁴ is C₁ or C₂ or C₃haloalkyl. In an exemplary embodiment, according to formula (I), R¹, R²,R³, R⁵, R⁶, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH—or —N(CH₂R⁷)—, and R⁴ is CF₃. In an exemplary embodiment, according toformula (I), R¹, R², R³, R⁵, R⁶, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁴ is hydrogen.

In an exemplary embodiment, according to formula (I), R¹, R², R³, R⁴,R⁶, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R⁵ is hydrogen or halogen or substituted orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀haloalkyl or substituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ orC₆ or C₇ or C₈ or C₉ or C₁₀ heteroalkyl. In an exemplary embodiment,according to formula (I), R¹, R², R³, R⁴, R⁶, and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁵ is halogen. Inan exemplary embodiment, according to formula (I), R¹, R², R³, R⁴, R⁶,and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R⁵ is fluorine or chlorine or bromine. In an exemplaryembodiment, according to formula (I), R¹, R², R³, R⁴, R⁶, and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁵ issubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C or C₉ or C₁₀alkyl. In an exemplary embodiment, according to formula (I), R¹, R², R³,R⁴, R⁶, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R⁵ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ orC₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment, according toformula (I), R¹, R², R³, R⁴, R⁶, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁵ is CH₃. In an exemplaryembodiment, according to formula (I), R¹, R², R³, R⁴, R⁶, and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁵ isunsubstituted C₁ or C₂ or C₃ or heteroalkyl. In an exemplary embodiment,according to formula (I), R¹, R², R³, R⁴, R⁶, and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁵ is C₁ or C₂ orC₃ alkoxy. In an exemplary embodiment, according to formula (I), R¹, R²,R³, R⁴, R⁶, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH—or —N(CH₂R⁷)—, and R⁵ is —OCH₃. In an exemplary embodiment, according toformula (I), R¹, R², R³, R⁴, R⁶, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁵ is C₁ or C₂ or C₃haloalkyl. In an exemplary embodiment, according to formula (I), R¹, R²,R³, R⁴, R⁶, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH—or —N(CH₂R⁷)—, and R⁵ is CF₃. In an exemplary embodiment, according toformula (I), R¹, R², R³, R⁴, R⁶, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁵ is hydrogen.

In an exemplary embodiment, according to formula (I), R¹, R², R³, R⁴,R⁵, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R⁶ is hydrogen or halogen or substituted orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₅ or C₉ or C₁₀haloalkyl or substituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ orC₆ or C₇ or C or C₉ or C₁₀ heteroalkyl. In an exemplary embodiment,according to formula (I), R¹, R², R³, R⁴, R⁵, and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁶ is halogen. Inan exemplary embodiment, according to formula (I), R¹, R², R³, R⁴, R⁵,and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R⁶ is fluorine or chlorine or bromine. In an exemplaryembodiment, according to formula (I), R¹, R², R³, R⁴, R⁵, and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁶ issubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl. In an exemplary embodiment, according to formula (I), R¹, R², R³,R⁴, R⁵, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R⁶ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ orC₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment, according toformula (I), R¹, R², R³, R⁴, R⁵, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁶ is CH₃. In an exemplaryembodiment, according to formula (I), R¹, R², R³, R⁴, R⁵, and R⁷ are asdescribed herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁶ isC₁ or C₂ or C₃ heteroalkyl. In an exemplary embodiment, according toformula (I), R¹, R², R³, R⁴, R⁵, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁶ is C₁ or C₂ or C₃ alkoxy.In an exemplary embodiment, according to formula (I), R¹, R², R³, R⁴,R⁵, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, and R⁶ is —OCH₃. In an exemplary embodiment, according toformula (I), R¹, R², R³, R⁴, R⁵, and R⁷ are as described herein, Y isC(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁶ is unsubstituted C₁ or C₂or C₃ haloalkyl. In an exemplary embodiment, according to formula (I),R¹, R², R³, R⁴, R⁵, and R⁷ are as described herein, Y is C(O), Z is —O—or —NH— or —N(CH₂R⁷)—, and R⁶ is CF₃. In an exemplary embodiment,according to formula (I), R¹, R², R³, R⁴, R⁵, and R⁷ are as describedherein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, and R⁶ is hydrogen.

In an exemplary embodiment, according to formula (I), R¹, R², R⁵, and R⁷are as described herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R³is halogen, and R⁴ is halogen. In an exemplary embodiment, according toformula (I), R¹, R², R⁵, and R⁷ are as described herein, Y is C(O), Z is—O— or —NH— or —N(CH₂R⁷)—, R³ is halogen, and R⁴ is fluorine orchlorine. In an exemplary embodiment, according to formula (I), R¹, R²,R⁵, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, R⁴ is halogen, and R³ is unsubstituted C₁ or C₂ or C₃ orheteroalkyl. In an exemplary embodiment, according to formula (I), R¹,R², R⁵, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH— or—N(CH₂R⁷)—, R³ is halogen, and R⁴ is C₁ or C₂ or C₃ alkoxy. In anexemplary embodiment, according to formula (I), R¹, R², R⁵, and R⁷ areas described herein, Y is C(O), Z is —O— or —NH— or —N(CH₂R)—, R³ isfluorine or chlorine, and R⁴ is —OCH₃. In an exemplary embodiment,according to formula (I), R¹, R², R⁵, and R⁷ are as described herein, Yis C(O), Z is —O— or —NH— or —N(CH₂R⁷)—, R⁴ is hydrogen, and R³ ishalogen or unsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ orC₉ or C₁₀ alkyl. In an exemplary embodiment, according to formula (I),R¹, R², R⁵, and R⁷ are as described herein, Y is C(O), Z is —O— or —NH—or —N(CH₂R⁷)—, R³ is hydrogen, and R⁴ is halogen or unsubstituted C₁ orC₂ or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ orC₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl.

In an exemplary embodiment, according to formula (I), R¹, R², R³, R⁴,R⁵, and R⁶ are as described herein, Y is C(O), Z is-N(CH₂R⁷)—, and R⁷ isunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl. In an exemplary embodiment, according to formula (I), R¹, R², R³,and R⁴ are as described herein, Y is C(O), Z is-N(CH₂R⁷)—, R⁵ is H, R⁶is H, and R⁷ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ orC₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment, according to formula(I), R¹, R², and R³ are as described herein, Y is C(O), Z is-N(CH₂R⁷)—,R⁴ is H, R⁵ is H, R⁶ is H, and R⁷ is unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₅ or C₉ or C₁₀ alkyl. In an exemplary embodiment,according to formula (I), R¹, R³, and R⁴ are as described herein, Y isC(O), Z is-N(CH₂R⁷)—, R² is H or F or CH₃, R⁵ is H, R⁶ is H, and R⁷ isunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl. In an exemplary embodiment, according to formula (I), R¹ and R³are as described herein, Y is C(O), Z is-N(CH₂R⁷)—, R² is H or F or CH₃,R⁴ is H, R⁵ is H, R⁶ is H, and R⁷ is unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment,according to formula (I), R¹ is as described herein, Y is C(O), Zis-N(CH₂R⁷)—, R² is H or F or CH₃, R³ is F, R⁴ is H, R⁵ is H, R⁶ is H,and R⁷ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ orC₉ or C₁₀ alkyl. In an exemplary embodiment, according to formula (I),R¹ is as described herein, Y is C(O), Z is-N(CH₂R⁷)—, R² is H or F orCH₃, R³ is F, R⁴ is H, R⁵ is H, R⁶ is H, and R⁷ is methyl or ethyl orpropyl or isopropyl. In an exemplary embodiment, according to formula(I), R¹, R², R³, R⁴, R⁵, and R⁶ are as described herein, Y is C(O), Zis-N(CH₂R⁷)—, and R⁷ is methyl or ethyl or propyl or isopropyl. In anexemplary embodiment, according to formula (I), R², R³, R⁴, R⁵, and R⁶are as described herein, Y is C(O), Z is-N(CH₂R⁷)—, R⁷ is unsubstitutedC₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl and R¹is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ orC₁₀ alkyl. In an exemplary embodiment, according to formula (I), R², R³,R⁴, R⁵, and R⁶ are as described herein, Y is C(O), Z is-N(CH₂R⁷)—, R⁷ ismethyl or ethyl or propyl or isopropyl and R¹ is unsubstituted C₁ or C₂or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplaryembodiment, according to formula (I), R², R³, R⁴, R⁵, and R⁶ are asdescribed herein, Y is C(O), Z is-N(CH₂R)—, R⁷ is unsubstituted C₁ or C₂or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl and R¹ is methylor ethyl or propyl or isopropyl. In an exemplary embodiment, accordingto formula (I), R², R³, R⁴, R⁵, and R⁶ are as described herein, Y isC(O), Z is-N(CH₂R⁷)—, R⁷ is methyl or ethyl or propyl or isopropyl andR¹ is methyl or ethyl or propyl or isopropyl. In an exemplaryembodiment, according to formula (I), R², R³, and R⁴ are as describedherein, Y is C(O), Z is-N(CH₂R⁷)—, R⁵ is H, R⁶ is H, and R⁷ is methyl orethyl or propyl or isopropyl and R¹ is methyl or ethyl or propyl orisopropyl. In an exemplary embodiment, according to formula (I), R² andR³ are as described herein, Y is C(O), Z is-N(CH₂R⁷)—, R⁴ is H, R⁵ is H,R⁶ is H, R¹ is methyl or ethyl or propyl or isopropyl and R⁷ is methylor ethyl or propyl or isopropyl. In an exemplary embodiment, accordingto formula (I), R³ and R⁴ are as described herein, Y is C(O), Zis-N(CH₂R⁷)—, R² is H or F or CH₃, R⁵ is H, R⁶ is H, R¹ is methyl orethyl or propyl or isopropyl and R⁷ is methyl or ethyl or propyl orisopropyl. In an exemplary embodiment, according to formula (I), R³ isas described herein, Y is C(O), Z is-N(CH₂R⁷)—, R² is H or F or CH₃, R⁴is H, R⁵ is H, R⁶ is H, R¹ is methyl or ethyl or propyl or isopropyl andR⁷ is methyl or ethyl or propyl or isopropyl. In an exemplaryembodiment, according to formula (I), Y is C(O), Z is-N(CH₂R⁷)—, R² is Hor F or CH₃, R³ is F, R⁴ is H, R⁵ is H, R⁶ is H, R¹ is methyl or ethylor propyl or isopropyl and R⁷ is methyl or ethyl or propyl or isopropyl.In an exemplary embodiment, according to formula (I), R¹ is as describedherein, Y is C(O), Z is-N(CH₂R⁷)—, R² is H or F or CH₃, R³ is F, R⁴ isH, R⁵ is H, R⁶ is H, and R⁷ is methyl or ethyl or propyl or isopropyl.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, has a structure which is

wherein R¹ and R² are as described herein. In an exemplary embodiment,the compound, or a salt or a hydrate or a solvate thereof, has astructure which is

wherein R¹ and R² are as described herein. In an exemplary embodiment,the compound, or a salt or a hydrate or a solvate thereof, has astructure which is

wherein R¹ and R² are as described herein.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, has a structure which is

wherein R² is as described herein. In an exemplary embodiment, thestructure is according to one of the following table, wherein R¹ is asdescribed herein, where applicable

Cmpd Form R² 1 II H 2 II F 3 II CH₃ 4 IIa H 5 IIa F 6 IIa CH₃ 7 III H 8III F 9 III CH₃ 10 IIIa H 11 IIIa F 12 IIIa CH₃ 13 IV H 14 IV F 15 IVCH₃ 16 IVa H 17 IVa F 18 IVa CH₃ 19 V H 20 V F 21 V CH₃ 22 Va H 23 Va F24 Va CH₃ 25 VI H 26 VI F 27 VI CH₃ 28 VIa H 29 VIa F 30 VIa CH₃ 31 VIIH 32 VII F 33 VII CH₃ 34 VIIa H 35 VIIa F 36 VIIa CH₃ 37 IIb H 38 IIb F39 IIb CH₃ 40 IVb H 41 IVb F 42 IVb CH₃ 43 VIb H 44 VIb F 45 VIb CH₃

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, has a structure which is

wherein R¹, R², R³, and R⁴ are as described herein.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, has a structure which is

wherein R¹, R², R³, and R⁴ are as described herein.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, has a structure which is

wherein R¹, R², R³, and R⁴ are as described herein.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, has a structure which is

wherein R¹, R², R³, and R⁴ are as described herein.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, has a structure which is

wherein R¹, R², and R³ are as described herein.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, has a structure which is

wherein R¹, R², and R³ are as described herein. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (XVIII) or (XIX) wherein R² is hydrogen or F orCl or unsubstituted C₁ or C₂ or C₃ alkyl; R³ is hydrogen orunsubstituted C₁ or C₂ or C₃ or alkyl or substituted or unsubstituted C₁or C₂ or C₃ alkoxy; and R¹ is as described herein. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (XVIII) or (XIX) wherein R² is H; R³ is F; andR¹ is as described herein.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, has a structure which is

wherein R² and R³ are as described herein.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, has a structure which is

wherein R² and R³ are as described herein.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, has a structure which is

wherein R² and R³ are as described herein.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, is according to formulae (Ia) or (VIII) or (VIIIb) or(IX) or (X) or (Xb) or (XI) or (XII) or (XIIb) or (XIII) or (XIV) or(XIVb) or (XV) or (XVI) or (XVIb) or (XVII) or (XX) or (XXI) or (XXII)or (XXIII), wherein R² is hydrogen or F or Cl or unsubstituted C₁ or C₂or C₃ alkyl; R³ is hydrogen or F or Cl or unsubstituted C₁ or C₂ or C₃or alkyl or substituted or unsubstituted C₁ or C₂ or C₃ alkoxy; and R⁴is hydrogen or F or Cl or unsubstituted C₁ or C₂ or C₃ or alkyl orsubstituted or unsubstituted C₁ or C₂ or C₃ alkoxy.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, is according to formulae (I) or (Ia) or (VIII) or(VIIIb) or (IX) or (X) or (Xb) or (XI) or (XII) or (XIIb) or (XIII) or(XIV) or (XIVb) or (XV) or (XVI) or (XVIb) or (XVII) or (XX) or (XXI) or(XXII) or (XXIII), wherein R² is H and R³ is H. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (Ia) or (VIII) or (VIIIb) or (IX) or (X)or (Xb) or (XI) or (XII) or (XIIb) or (XIII) or (XIV) or (XIVb) or (XV)or (XVI) or (XVIb) or (XVII) or (XX) or (XXI) or (XXII) or (XXIII),wherein R² is F and R³ is H. In an exemplary embodiment, the compound,or a salt or a hydrate or a solvate thereof, is according to formulae(I) or (Ia) or (VIII) or (VIIIb) or (IX) or (X) or (Xb) or (XI) or (XII)or (XIIb) or (XIII) or (XIV) or (XIVb) or (XV) or (XVI) or (XVIb) or(XVII) or (XX) or (XXI) or (XXII) or (XXIII), wherein R² is H and R³ isF. In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, is according to formula (XVIb), wherein R² is H and R³is F. In an exemplary embodiment, the compound, or a salt or a hydrateor a solvate thereof, is according to formulae (I) or (Ia) or (VIII) or(VIIIb) or (IX) or (X) or (Xb) or (XI) or (XII) or (XIIb) or (XIII) or(XIV) or (XIVb) or (XV) or (XVI) or (XVIb) or (XVII) or (XX) or (XXI) or(XXII) or (XXIII), wherein R² is F and R³ is F. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (Ia) or (VIII) or (VIIIb) or (IX) or (X)or (Xb) or (XI) or (XII) or (XIIb) or (XIII) or (XIV) or (XIVb) or (XV)or (XVI) or (XVIb) or (XVII) or (XX) or (XXI) or (XXII) or (XXIII),wherein R² is H and R³ is Cl. In an exemplary embodiment, the compound,or a salt or a hydrate or a solvate thereof, is according to formulae(I) or (Ia) or (VIII) or (VIIIb) or (IX) or (X) or (Xb) or (XI) or (XII)or (XIIb) or (XIII) or (XIV) or (XIVb) or (XV) or (XVI) or (XVIb) or(XVII) or (XX) or (XXI) or (XXII) or (XXIII), wherein R² is F and R³ isCl. In an exemplary embodiment, the compound, or a salt or a hydrate ora solvate thereof, is according to formulae (I) or (Ia) or (VIII) or(VIIIb) or (IX) or (X) or (Xb) or (XI) or (XII) or (XIIb) or (XIII) or(XIV) or (XIVb) or (XV) or (XVI) or (XVIb) or (XVII) or (XX) or (XXI) or(XXII) or (XXIII), wherein R² is H and R³ is —OCH₃. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (Ia) or (VIII) or (VIIIb) or (IX) or (X)or (Xb) or (XI) or (XII) or (XIIb) or (XIII) or (XIV) or (XIVb) or (XV)or (XVI) or (XVIb) or (XVII) or (XX) or (XXI) or (XXII) or (XXIII),wherein R² is H and R³ is —OCHF₂. In an exemplary embodiment, thecompound, or a salt or a hydrate or a solvate thereof, is according toformulae (I) or (Ia) or (VIII) or (VIIIb) or (IX) or (X) or (Xb) or (XI)or (XII) or (XIIb) or (XIII) or (XIV) or (XIVb) or (XV) or (XVI) or(XVIb) or (XVII) or (XX) or (XXI) or (XXII) or (XXIII), wherein R² is Hand R³ is —OCF₃. In an exemplary embodiment, the compound, or a salt ora hydrate or a solvate thereof, is according to formulae (I) or (Ia) or(VIII) or (VIIIb) or (IX) or (X) or (Xb) or (XI) or (XII) or (XIIb) or(XIII) or (XIV) or (XIVb) or (XV) or (XVI) or (XVIb) or (XVII) or (XX)or (XXI) or (XXII) or (XXIII), wherein R² is H and R³ is —CH₃. In anexemplary embodiment, the compound, or a salt or a hydrate or a solvatethereof, is according to formulae (I) or (Ia) or (VIII) or (VIIIb) or(IX) or (X) or (Xb) or (XI) or (XII) or (XIIb) or (XIII) or (XIV) or(XIVb) or (XV) or (XVI) or (XVIb) or (XVII) or (XX) or (XXI) or (XXII)or (XXIII), wherein R² is H and R³ is —CF₃. In an exemplary embodiment,the compound, or a salt or a hydrate or a solvate thereof, is accordingto formulae (I) or (Ia) or (VIII) or (VIIIb) or (IX) or (X) or (Xb) or(XI) or (XII) or (XIIb) or (XIII) or (XIV) or (XIVb) or (XV) or (XVI) or(XVIb) or (XVII) or (XX) or (XXI) or (XXII) or (XXIII), wherein R² is Hand R³ is —OCH₂CH₃. In an exemplary embodiment, the compound, or a saltor a hydrate or a solvate thereof, is according to formulae (I) or(VIII) or (IX) or (X) or (XI) or (XII) or (XIII) or (XIV) or (XV) or(XVI) or (XVII) or (XVIII) or (XIX) or (XX) or (XXI) or (XXII) or(XXIII), wherein R¹ is substituted or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl or substituted orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀heteroalkyl or substituted or unsubstituted aryl or substituted orunsubstituted arylalkyl or substituted or unsubstituted cycloalkyl orsubstituted or unsubstituted heterocycloalkyl. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (VIII) or (IX) or (X) or (XI) or (XII)or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or(XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is methyl. In anexemplary embodiment, the compound, or a salt or a hydrate or a solvatethereof, is according to formulae (I) or (VIII) or (IX) or (X) or (XI)or (XII) or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or(XIX) or (XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is ethyl. In anexemplary embodiment, the compound, or a salt or a hydrate or a solvatethereof, is according to formulae (I) or (VIII) or (IX) or (X) or (XI)or (XII) or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or(XIX) or (XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is—(CH₂)_(m)OR^(1a), wherein R^(1a) is substituted or unsubstituted C₁ orC₂ or C₃ alkyl, and m is 1 or 2 or 3. In an exemplary embodiment, thecompound, or a salt or a hydrate or a solvate thereof, is according toformulae (I) or (VIII) or (IX) or (X) or (XI) or (XII) or (XIII) or(XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or (XX) or (XXI) or(XXII) or (XXIII), wherein R¹ is —(CH₂)₂OCH₃. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (VIII) or (IX) or (X) or (XI) or (XII)or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or(XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is propyl or —CH₂CH₂F or—CH₂CHF₂ or —CH₂CF₃ or —CH(CH₃)₂ or —CH(CH₃)(CH₂CH₃) or cyclopropyl orcyclobutyl or cyclopentyl or cyclohexyl or oxetanyl or tetrahydropyranylor azetidinyl or methylazetidinyl or piperidinyl or methylpiperidinyl orphenyl or benzyl or —(CH₂)_(m)NR^(1b)R^(1c), wherein R^(1b) is hydrogenor substituted or unsubstituted C₁ or C₂ or C₃ alkyl and R^(1c) ishydrogen or substituted or unsubstituted C₁ or C₂ or C₃ alkyl and m is 1or 2 or 3, with the proviso that R^(1b) and R^(1c) can optionally bejoined to form a 4-7 membered ring.

In an exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, is according to formulae (I) or (VIII) or (IX) or (X)or (XI) or (XII) or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or(XVIII) or (XIX) or (XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is—(CH₂)₂OCH₃, R² is H, and R³ is H. In an exemplary embodiment, thecompound, or a salt or a hydrate or a solvate thereof, is according toformulae (I) or (VIII) or (IX) or (X) or (XI) or (XII) or (XIII) or(XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or (XX) or (XXI) or(XXII) or (XXIII), wherein R¹ is —(CH₂)₂OCH₃, R² is H, and R³ is F. Inan exemplary embodiment, the compound, or a salt or a hydrate or asolvate thereof, is according to formulae (I) or (VIII) or (IX) or (X)or (XI) or (XII) or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or(XVIII) or (XIX) or (XX) or (XXI) or (XXII) or (XXIII), wherein R¹ ismethyl, R² is F, and R³ is F. In an exemplary embodiment, the compound,or a salt or a hydrate or a solvate thereof, is according to formulae(I) or (VIII) or (IX) or (X) or (XI) or (XII) or (XIII) or (XIV) or (XV)or (XVI) or (XVII) or (XVIII) or (XIX) or (XX) or (XXI) or (XXII) or(XXIII), wherein R¹ is ethyl, R² is F, and R³ is F. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (VIII) or (IX) or (X) or (XI) or (XII)or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or(XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is —(CH₂)₂OCH₃, R² is F,and R³ is F. In an exemplary embodiment, the compound, or a salt or ahydrate or a solvate thereof, is according to formulae (I) or (VIII) or(IX) or (X) or (XI) or (XII) or (XIII) or (XIV) or (XV) or (XVI) or(XVII) or (XVIII) or (XIX) or (XX) or (XXI) or (XXII) or (XXIII),wherein R¹ is methyl; R² is H; and R³ is —CH₃. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (VIII) or (IX) or (X) or (XI) or (XII)or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or(XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is ethyl; R² is H; and R³is —CH₃. In an exemplary embodiment, the compound, or a salt or ahydrate or a solvate thereof, is according to formulae (I) or (VIII) or(IX) or (X) or (XI) or (XII) or (XIII) or (XIV) or (XV) or (XVI) or(XVII) or (XVIII) or (XIX) or (XX) or (XXI) or (XXII) or (XXIII),wherein R¹ is —(CH₂)₂OCH₃, R² is H; and R³ is —CH₃. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (VIII) or (IX) or (X) or (XI) or (XII)or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or(XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is methyl; R² is H; andR³ is —OCH₃. In an exemplary embodiment, the compound, or a salt or ahydrate or a solvate thereof, is according to formulae (I) or (VIII) or(IX) or (X) or (XI) or (XII) or (XIII) or (XIV) or (XV) or (XVI) or(XVII) or (XVIII) or (XIX) or (XX) or (XXI) or (XXII) or (XXIII),wherein R¹ is ethyl; R² is H; and R³ is —OCH₃. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (VIII) or (IX) or (X) or (XI) or (XII)or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or(XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is —(CH₂)₂OCH₃, R² is H;and R³ is —OCH₃. In an exemplary embodiment, the compound, or a salt ora hydrate or a solvate thereof, is according to formulae (I) or (VIII)or (IX) or (X) or (XI) or (XII) or (XIII) or (XIV) or (XV) or (XVI) or(XVII) or (XVIII) or (XIX) or (XX) or (XXI) or (XXII) or (XXIII),wherein R¹ is methyl; R² is H; and R³ is —OCHF₂. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (VIII) or (IX) or (X) or (XI) or (XII)or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or(XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is ethyl; R² is H; and R³is —OCHF₂. In an exemplary embodiment, the compound, or a salt or ahydrate or a solvate thereof, is according to formulae (I) or (VIII) or(IX) or (X) or (XI) or (XII) or (XIII) or (XIV) or (XV) or (XVI) or(XVII) or (XVIII) or (XIX) or (XX) or (XXI) or (XXII) or (XXIII),wherein R¹ is —(CH₂)₂OCH₃, R² is H; and R³ is —OCHF₂. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (VIII) or (IX) or (X) or (XI) or (XII)or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or(XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is methyl; R² is H; andR³ is —OCH₂CH₃. In an exemplary embodiment, the compound, or a salt or ahydrate or a solvate thereof, is according to formulae (I) or (VIII) or(IX) or (X) or (XI) or (XII) or (XIII) or (XIV) or (XV) or (XVI) or(XVII) or (XVIII) or (XIX) or (XX) or (XXI) or (XXII) or (XXIII),wherein R¹ is ethyl; R² is H; and R³ is —OCH₂CH₃. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (VIII) or (IX) or (X) or (XI) or (XII)or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or(XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is —(CH₂)₂OCH₃, R² is H;and R³ is —OCH₂CH₃. In an exemplary embodiment, the compound, or a saltor a hydrate or a solvate thereof, is according to formulae (I) or(VIII) or (IX) or (X) or (XI) or (XII) or (XIII) or (XIV) or (XV) or(XVI) or (XVII) or (XVIII) or (XIX) or (XX) or (XXI) or (XXII) or(XXIII), wherein R¹ is methyl; R² is H; and R³ is F. In an exemplaryembodiment, the compound, or a salt or a hydrate or a solvate thereof,is according to formulae (I) or (VIII) or (IX) or (X) or (XI) or (XII)or (XIII) or (XIV) or (XV) or (XVI) or (XVII) or (XVIII) or (XIX) or(XX) or (XXI) or (XXII) or (XXIII), wherein R¹ is ethyl; R² is H; and R³is F.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(I):

wherein Y is C(O) or S(O)₂; Z is —O— or —CH₂— or —NH— or —N(CH₂R⁷)—wherein R⁷ is hydrogen or substituted or unsubstituted C₁ or C₂ or C₃ orC₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl; R¹ is hydrogen orsubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ orC₈ or C₉ or C₁₀ alkyl or substituted or unsubstituted aryl or arylalkyl;R² is hydrogen or halogen or substituted or unsubstituted C₁ or C₂ or C₃or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl; R³ is hydrogen orhalogen or substituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆or C₇ or C₈ or C₉ or C₁₀ alkyl; R⁴ is hydrogen or halogen or substitutedor unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₅ or C₉ orC₁₀ alkyl; R⁵ is hydrogen or halogen or substituted or unsubstituted C₁or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl; and R⁶ ishydrogen or halogen or substituted or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl.

In an exemplary embodiment, for a formula described herein, Y, Z, R²,R³, R⁴, R⁵, and R⁶ are as described herein, R¹ is unsubstituted C₁ or C₂or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplaryembodiment, for a formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶are as described herein, R¹ is methyl or ethyl. In an exemplaryembodiment, for a formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶are as described herein, R¹ is n-propyl or isopropyl or n-butyl ort-butyl or isobutyl or sec-butyl. In an exemplary embodiment, for aformula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as describedherein, R¹ is cyclopropyl or cyclopropylmethyl or cyclobutyl orcyclohexyl. In an exemplary embodiment, for a formula described herein,Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ is substitutedC₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In anexemplary embodiment, for a formula described herein, Y, Z, R², R³, R⁴,R⁵, and R⁶ are as described herein, R¹ is substituted or unsubstitutedC₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ haloalkyl orsubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ orC₈ or C₉ or C₁₀ heteroalkyl. In an exemplary embodiment, for a formuladescribed herein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein,R¹ is substituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ orC₇ or C₈ or C₉ or C₁₀ haloalkyl. In an exemplary embodiment, for aformula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as describedherein, R¹ is C₁ or C₂ or C₃ haloalkyl. In an exemplary embodiment, fora formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are asdescribed herein, R¹ is 2-fluoroethyl or 2,2-difluoroethyl or2,2,2-trifluoroethyl or 2-chloroethyl or 3-chloropropyl. In an exemplaryembodiment, for a formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶are as described herein, R¹ is C₁-C₄ alkyl substituted withNR^(8a)R^(8b), wherein R^(8a) and R^(8b) are each independentlysubstituted or unsubstituted C₁-C₄ alkyl. In an exemplary embodiment,for a formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are asdescribed herein, R¹ is C₁-C₄ alkyl substituted with N(CH₃)₂. In anexemplary embodiment, for a formula described herein, Y, Z, R², R³, R⁴,R⁵, and R⁶ are as described herein, R¹ is C₁-C₄ alkyl substituted withN(CH₂CH₃)₂. In an exemplary embodiment, for a formula described herein,Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ is alkylsubstituted with substituted or unsubstituted heterocycloalkyl. In anexemplary embodiment, for a formula described herein, Y, Z, R², R³, R⁴,R⁵, and R⁶ are as described herein, R¹ is C₁-C₄ alkyl substituted withsubstituted pyrrolidinyl or substituted piperazinyl or substitutedmorpholinyl or substituted piperidinyl or substituted pyrrolidinyl. Inan exemplary embodiment, for a formula described herein, Y, Z, R², R³,R⁴, R⁵, and R⁶ are as described herein, R¹ is C₁-C₄ alkyl substitutedwith unsubstituted pyrrolidinyl or unsubstituted piperazinyl orunsubstituted morpholinyl or unsubstituted piperidinyl or unsubstitutedpyrrolidinyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ isalkyl substituted with substituted or unsubstituted C₃-C₇ cycloalkyl. Inan exemplary embodiment, for a formula described herein, Y, Z, R², R³,R⁴, R⁵, and R⁶ are as described herein, R¹ is substituted orunsubstituted aryl. In an exemplary embodiment, for a formula describedherein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ isphenyl. In an exemplary embodiment, for a formula described herein, Y,Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ is substituted orunsubstituted arylalkyl. In an exemplary embodiment, for a formuladescribed herein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein,R¹ is benzyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ issubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or Cor C₉ or C₁₀ heteroalkyl. In an exemplary embodiment, for a formuladescribed herein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein,R¹ is —CH₂—CH₂—O—CH₃ or —CH₂—CH₂—N(CH₃)—CH₃ or —CH₂—CH₂—CH₂—N(CH₃)—CH₃.In an exemplary embodiment, for a formula described herein, Y, Z, R²,R³, R⁴, R⁵, and R⁶ are as described herein, R¹ is unsubstituted C₁ or C₂or C₃ heteroalkyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ issubstituted or unsubstituted C₃ or C₄ or C₅ or C₆ or C₇ or C₈heterocycloalkyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ issubstituted or unsubstituted oxetanyl. In an exemplary embodiment, for aformula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as describedherein, R¹ is substituted or unsubstituted tetrahydropyranyl. In anexemplary embodiment, for a formula described herein, Y, Z, R², R³, R⁴,R⁵, and R⁶ are as described herein, R¹ is substituted or unsubstitutedazetidinyl. In an exemplary embodiment, for a formula described herein,Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ is substitutedor unsubstituted methylazetidinyl or substituted or unsubstitutedethylazetidinyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ issubstituted or unsubstituted piperidinyl. In an exemplary embodiment,for a formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are asdescribed herein, R¹ is substituted or unsubstituted methylpiperidinylor substituted or unsubstituted ethylpiperidinyl. In an exemplaryembodiment, for a formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶are as described herein, R¹ is 2-(4-methylpiperazin-1-yl)ethyl or3-(4-methylpiperazin-1-yl)propyl or 2-morpholinoethyl or3-morpholinopropyl or 1-methylazetidin-3-yl or 1-ethylazetidin-3-yl or1-isopropylazetidin-3-yl or 1-methylpiperidin-4-yl or1-ethylpiperidin-4-yl or 1-isopropylpiperidin-4-yl. In an exemplaryembodiment, for a formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶are as described herein, R¹ is —(CH₂)_(m)OR^(1a), wherein R¹ a issubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ alkyl, andm is 4 or 5 or 6. In an exemplary embodiment, for a formula describedherein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ is—(CH₂)_(m)OR^(1a), wherein R^(1a) is substituted or unsubstituted C₁ orC₂ or C₃ or C₄ or C₅ or C₆ alkyl, and m is 1 or 2 or 3. In an exemplaryembodiment, for a formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶are as described herein, R¹ is —(CH₂)_(m)OR^(1a), wherein R¹ a issubstituted or unsubstituted C₁ or C₂ or C₃, and m is 1 or 2 or 3 or 4or 5 or 6. In an exemplary embodiment, for a formula described herein,Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ is—(CH₂)_(m)OR^(1a), wherein R^(1a) is substituted or unsubstituted C₄ orC₅ or C₆, and m is 1 or 2 or 3 or 4 or 5 or 6. In an exemplaryembodiment, for a formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶are as described herein, R¹ is —(CH₂)_(m)OR^(1a), wherein R¹ a issubstituted or unsubstituted C₁ or C₂ or C₃, and m is 1 or 2 or 3. In anexemplary embodiment, for a formula described herein, Y, Z, R², R³, R⁴,R⁵, and R⁶ are as described herein, R¹ is —(CH₂)_(m)OR^(1a), whereinR^(1a) is methyl, and m is 1 or 2 or 3. In an exemplary embodiment, fora formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are asdescribed herein, R¹ is —(CH₂)_(m)OR^(1a), wherein R¹ a is ethyl, and mis 1 or 2 or 3. In an exemplary embodiment, for a formula describedherein, Y, Z, R², R³, R⁴, R⁵, and R⁶ are as described herein, R¹ is—(CH₂)_(m)OR^(1a), wherein R¹ a is methyl, and m is 2. In an exemplaryembodiment, for a formula described herein, Y, Z, R², R³, R⁴, R⁵, and R⁶are as described herein, R¹ is —(CH₂)_(m)OR^(1a), wherein R¹ a is ethyl,and m is 2.

In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R³, R⁴, R⁵, and R⁶ are as described herein, R² is substituted C₁ or C₂or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R³, R⁴, R⁵, and R⁶are as described herein, R² is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment, for aformula described herein, Y, Z, R¹, R³, R⁴, R⁵, and R⁶ are as describedherein, R² is CH₃. In an exemplary embodiment, for a formula describedherein, Y, Z, R¹, R³, R⁴, R⁵, and R⁶ are as described herein, R² is H.In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R³, R⁴, R⁵, and R⁶ are as described herein, R² is halogen. In anexemplary embodiment, for a formula described herein, Y, Z, R¹, R³, R⁴,R⁵, and R⁶ are as described herein, R² is fluorine or chlorine. In anexemplary embodiment, for a formula described herein, Y, Z, R¹, R³, R⁴,R⁵, and R⁶ are as described herein, R² is chlorine.

In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R⁴, R⁵, and R⁶ are as described herein, R³ is hydrogen or halogen orsubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ orC₈ or C₉ or C₁₀ haloalkyl or substituted or unsubstituted C₁ or C₂ or C₃or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ heteroalkyl. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R², R⁴, R⁵, and R⁶are as described herein, R³ is substituted C₁ or C₂ or C₃ or C₄ or C₅ orC₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment, for aformula described herein, Y, Z, R¹, R², R⁴, R⁵, and R⁶ are as describedherein, R³ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈or C₉ or C₁₀ alkyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R¹, R², R⁴, R⁵, and R⁶ are as described herein, R³ is CH₃.In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R⁴, R⁵, and R⁶ are as described herein, R³ is unsubstituted C₁ or C₂or C₃ heteroalkyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R¹, R², R³, R⁴, R⁵, and R⁶ are as described herein, R³ isC₁ or C₂ or C₃ alkoxy. In an exemplary embodiment, for a formuladescribed herein, Y, Z, R¹, R², R⁴, R⁵, and R⁶ are as described herein,R³ is —OCH₃. In an exemplary embodiment, for a formula described herein,Y, Z, R¹, R², R⁴, R⁵, and R⁶ are as described herein, R³ is C₁ or C₂ orC₃ haloalkyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R¹, R², R³, R⁴, R⁵, and R⁶ are as described herein, R³ isCF₃. In an exemplary embodiment, for a formula described herein, Y, Z,R¹, R², R⁴, R⁵, and R⁶ are as described herein, R³ is H. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R², R⁴, R⁵, and R⁶are as described herein, R³ is halogen. In an exemplary embodiment, fora formula described herein, Y, Z, R¹, R², R³, R⁴, R⁵, and R⁶ are asdescribed herein, R³ is fluorine or chlorine. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R², R⁴, R⁵, and R⁶are as described herein, R³ is fluorine.

In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R³, R⁵, and R⁶ are as described herein, R⁴ is hydrogen or halogen orsubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ orC₈ or C₉ or C₁₀ haloalkyl or substituted or unsubstituted C₁ or C₂ or C₃or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ heteroalkyl. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R², R³, R⁵, and R⁶are as described herein, R⁴ is halogen. In an exemplary embodiment, fora formula described herein, Y, Z, R¹, R², R³, R⁵, and R⁶ are asdescribed herein, R⁴ is fluorine or chlorine. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R², R³, R⁵, and R⁶are as described herein, R⁴ is substituted C₁ or C₂ or C₃ or C₄ or C₅ orC₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment, for aformula described herein, Y, Z, R¹, R², R³, R⁵, and R⁶ are as describedherein, R⁴ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈or C₉ or C₁₀ alkyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R¹, R², R³, R⁵, and R⁶ are as described herein, R⁴ is CH₃.In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R³, R⁵, and R⁶ are as described herein, R⁴ is unsubstituted C₁ or C₂or C₃ or heteroalkyl. In an exemplary embodiment, for a formuladescribed herein, Y, Z, R¹, R², R³, R⁵, and R⁶ are as described herein,R⁴ is C₁ or C₂ or C₃ alkoxy. In an exemplary embodiment, for a formuladescribed herein, Y, Z, R¹, R², R³, R⁵, and R⁶ are as described herein,R⁴ is —OCH₃. In an exemplary embodiment, for a formula described herein,Y, Z, R¹, R², R³, R⁵, and R⁶ are as described herein, R⁴ is C₁ or C₂ orC₃ haloalkyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R¹, R², R³, R⁵, and R⁶ are as described herein, R⁴ is CF₃.In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R³, R⁵, and R⁶ are as described herein, R⁴ is hydrogen.

In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R⁵, and R⁶ are as described herein, R³ is halogen and R⁴ is halogen.In an exemplary embodiment, for a formula described herein, for aformula described herein, Y, Z, R¹, R², R⁵, and R⁶ are as describedherein, R³ is halogen and R⁴ is fluorine or chlorine. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R², R⁵, and R⁶ areas described herein, R⁴ is halogen and R³ is unsubstituted C₁ or C₂ orC₃ or heteroalkyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R¹, R², R⁵, and R⁶ are as described herein, R³ is halogenand R⁴ is C₁ or C₂ or C₃ alkoxy. In an exemplary embodiment, for aformula described herein, Y, Z, R¹, R², R⁵, and R⁶ are as describedherein, R³ is fluorine or chlorine and R⁴ is —OCH₃. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R², R⁵, and R⁶ areas described herein, R⁴ is hydrogen and R³ is halogen or unsubstitutedC₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ orC₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In anexemplary embodiment, for a formula described herein, Y, Z, R¹, R², R⁵,and R⁶ are as described herein, R³ is hydrogen and R⁴ is halogen orunsubstituted C₁ or C₂ or C₃ haloalkyl or C₁ or C₂ or C₃ alkoxy orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl.

In an exemplary embodiment, for formula (VIII) or (IX) or (X) or (XI) or(XII) or (XIII) or (XIV) or (XV), Y, Z, R¹, R², R⁵, and R⁶ are asdescribed herein, R³ is F or Cl or CH₃ or OCH₃ and R⁴ is F or Cl or CH₃or OCH₃. In an exemplary embodiment, for formula (VIII) or (IX) or (X)or (XI) or (XII) or (XIII) or (XIV) or (XV), Y, Z, R¹, R², R⁵, and R⁶are as described herein, R³ is F and R⁴ is F or C1 or CH₃ or OCH₃. In anexemplary embodiment, for formula (VIII) or (IX) or (X) or (XI) or (XII)or (XIII) or (XIV) or (XV), Y, Z, R¹, R², R⁵, and R⁶ are as describedherein, R³ is CH₃ and R⁴ is F or Cl or CH₃ or OCH₃. In an exemplaryembodiment, for formula (VIII) or (IX) or (X) or (XI) or (XII) or (XIII)or (XIV) or (XV), Y, Z, R¹, R², R⁵, and R⁶ are as described herein, R³is OCH₃ and R⁴ is F. In an exemplary embodiment, for formula (Ia) or(VIIIb) or (Xb) or (XIIb) or (XIVb) or (XVIb), Y, Z, R¹, R², R⁵, and R⁶are as described herein, R³ is F and R⁴ is OCH₃. In an exemplaryembodiment, for formula (Ia) or (VIIIb) or (Xb) or (XIIb) or (XIVb) or(XVIb), Y, Z, R¹, R², R⁵, and R⁶ are as described herein, R³ is OCH₃ andR⁴ is F.

In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R³, R⁴, and R⁶ are as described herein, R⁵ is hydrogen or halogen orsubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ orC₈ or C₉ or C₁₀ haloalkyl or substituted or unsubstituted C₁ or C₂ or C₃or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ heteroalkyl. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R², R³, R⁴, and R⁶are as described herein, R⁵ is halogen. In an exemplary embodiment, fora formula described herein, Y, Z, R¹, R², R³, R⁴, and R⁶ are asdescribed herein, R⁵ is fluorine or chlorine or bromine. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R², R³, R⁴, and R⁶are as described herein, R⁵ is substituted C₁ or C₂ or C₃ or C₄ or C₅ orC₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment, for aformula described herein, Y, Z, R¹, R², R³, R⁴, and R⁶ are as describedherein, R⁵ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈or C₉ or C₁₀ alkyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R¹, R², R³, R⁴, and R⁶ are as described herein, R⁵ is CH₃.In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R³, R⁴, and R⁶ are as described herein, R⁵ is unsubstituted C₁ or C₂or C₃ or heteroalkyl. In an exemplary embodiment, for a formuladescribed herein, Y, Z, R¹, R², R³, R⁴, and R⁶ are as described herein,R⁵ is C₁ or C₂ or C₃ alkoxy. In an exemplary embodiment, for a formuladescribed herein, Y, Z, R¹, R², R³, R⁴, and R⁶ are as described herein,R⁵ is —OCH₃. In an exemplary embodiment, for a formula described herein,Y, Z, R¹, R², R³, R⁴, and R⁶ are as described herein, R⁵ is C₁ or C₂ orC₃ haloalkyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R¹, R², R³, R⁴, and R⁶ are as described herein, R⁵ is CF₃.In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R³, R⁴, and R⁶ are as described herein, R⁵ is hydrogen.

In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R³, R⁴, and R⁵ are as described herein, R⁶ is hydrogen or halogen orsubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ orC₈ or C₉ or C₁₀ haloalkyl or substituted or unsubstituted C₁ or C₂ or C₃or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ heteroalkyl. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R², R³, R⁴, and R⁵are as described herein, R⁶ is halogen. In an exemplary embodiment, fora formula described herein, Y, Z, R¹, R², R³, R⁴, and R⁵ are asdescribed herein, R⁶ is fluorine or chlorine or bromine. In an exemplaryembodiment, for a formula described herein, Y, Z, R¹, R², R³, R⁴, and R⁵are as described herein, R⁶ is substituted C₁ or C₂ or C₃ or C₄ or C₅ orC₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment, for aformula described herein, Y, Z, R¹, R², R³, R⁴, and R⁵ are as describedherein, R⁶ is unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₅or C₉ or C₁₀ alkyl. In an exemplary embodiment, for a formula describedherein, Y, Z, R¹, R², R³, R⁴, and R⁵ are as described herein, R⁶ is CH₃.In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R³, R⁴, and R⁵ are as described herein, R⁶ is C₁ or C₂ or C₃heteroalkyl. In an exemplary embodiment, for a formula described herein,Y, Z, R¹, R², R³, R⁴, and R⁵ are as described herein, R⁶ is C₁ or C₂ orC₃ alkoxy. In an exemplary embodiment, for a formula described herein,Y, Z, R¹, R², R³, R⁴, and R⁵ are as described herein, R⁶ is —OCH₃. In anexemplary embodiment, for a formula described herein, Y, Z, R¹, R², R³,R⁴, and R⁵ are as described herein, R⁶ is unsubstituted C₁ or C₂ or C₃haloalkyl. In an exemplary embodiment, for a formula described herein,Y, Z, R¹, R², R³, R⁴, and R⁵ are as described herein, R⁶ is CF₃. In anexemplary embodiment, for a formula described herein, Y, Z, R¹, R², R³,R⁴, R⁵, and R⁶ are as described herein, R⁶ is hydrogen.

In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R³, and R⁴ are as described herein, R⁵ is halogen and R⁶ is halogen.In an exemplary embodiment, for a formula described herein, Y, Z, R¹,R², R³, R⁴, R⁵, and R⁶ are as described herein, R⁵ is halogen and R⁶ isfluorine or chlorine. In an exemplary embodiment, for a formuladescribed herein, Y, Z, R¹, R², R³, and R⁴ are as described herein, R⁵is hydrogen and R⁶ is halogen or unsubstituted C₁ or C₂ or C₃ haloalkylor C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ orC₆ or C₇ or C₈ or C₉ or C₁₀ alkyl. In an exemplary embodiment, for aformula described herein, Y, Z, R¹, R², R³, and R⁴ are as describedherein, R⁶ is hydrogen and R⁵ is halogen or unsubstituted C₁ or C₂ or C₃haloalkyl or C₁ or C₂ or C₃ alkoxy or unsubstituted C₁ or C₂ or C₃ or C₄or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to thefollowing formula:

wherein R⁵ is F or CH₃.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to thefollowing formula:

wherein R⁵ is F or Cl or CH₃ or CF₃ or OCH₃.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to thefollowing formula:

wherein R⁵ is F or Cl or CH₃ or CF₃ or OCH₃ or OCF₃.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to thefollowing formula:

wherein R⁵ is F or Cl or CH₃ or CF₃ or OCH₃.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to thefollowing formula:

wherein R⁵ is F and R⁶ is F

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to thefollowing formula:

wherein R⁵ is F and R⁶ is F or R⁵ is OCH₃ and R⁶ is OCH₃.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to thefollowing formula:

wherein R⁵ is F and R⁶ is F or R⁵ is OCH₃ and R⁶ is OCH₃.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to thefollowing formula:

wherein R³ is as described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXV):

wherein Y, Z, R¹, R², and R³ are as described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXVI):

wherein Y, Z, R¹, R², and R³ are as described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXVII):

wherein Y, Z, R¹, R², and R³ are as described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXVIII):

wherein Y, Z, R¹, R², and R³ are as described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXIX):

wherein Y, Z, R¹, R³, and R⁵ are as described herein. In an exemplaryembodiment, the compound is according to formula (XXIX), wherein Y isC(O), Z is O or NH, R¹ is ethyl, R³ is F, and R⁵ is as described herein.In an exemplary embodiment, the compound is according to formula (XXIX),wherein Y is C(O), Z is O or NH, R¹ is methyl, R³ is F, and R⁵ is asdescribed herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXX):

wherein Y, Z, R¹, R³, R⁵, and R⁶ are as described herein. In anexemplary embodiment, the compound is according to formula (XXX),wherein Y is C(O), Z is O or NH, R¹ is ethyl, R³ is F, and R⁵ and R⁶ areas described herein. In an exemplary embodiment, the compound isaccording to formula (XXX), wherein Y is C(O), Z is O or NH, R¹ ismethyl, R³ is F, and R⁵ and R⁶ are as described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXXI):

wherein Y, Z, R¹, R³, R⁵, and R⁶ are as described herein. In anexemplary embodiment, the compound is according to formula (XXXI),wherein Y is C(O), Z is O or NH, R¹ is ethyl, R³ is F, and R⁵ and R⁶ areas described herein. In an exemplary embodiment, the compound isaccording to formula (XXXI), wherein Y is C(O), Z is O or NH, R¹ ismethyl, R³ is F, and R⁵ and R⁶ are as described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXXII):

wherein Y, Z, R¹, R³, and R⁴ are as described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXXIII):

wherein Y, Z, R¹, R³, and R⁴ are as described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXXIV):

wherein Y, Z, R¹, R³, and R⁴ are as described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXXV):

wherein Y, Z, R¹, R², R³, R⁴, R⁵, and R⁶ are as described herein.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXXVI):

wherein R¹, R², R³, and R⁴ are as described herein. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R¹,R², and R³ are as described herein, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R¹ andR² are as described herein, R³ is H and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R¹ andR² are as described herein, R³ is F and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R¹ andR² are as described herein, R³ is Cl and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R¹ andR² are as described herein, R³ is C₁ or C₂ or C₃ alkyl and R⁴ is H. Inan exemplary embodiment, the compound is according to formula (XXXVI),wherein R¹ and R² are as described herein, R³ is C₁ or C₂ or C₃ alkoxyand R⁴ is H. In an exemplary embodiment, the compound is according toformula (XXXVI), wherein R¹ and R² are as described herein, R³ ishalogen-substituted C₁ or C₂ or C₃ alkoxy and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R¹ isas described herein, R² is H, R³ is H, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R¹ andR³ are as described herein, R² is H and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R²,R³, and R⁴ are as described herein, and R¹ is methyl. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R² andR³ are as described herein, R¹ is methyl, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R² isas described herein, R¹ is methyl, R³ is H, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R³ isas described herein, R¹ is methyl, R² is H, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R³ ismethyl, R¹ is methyl, R² is H, and R⁴ is H. In an exemplary embodiment,the compound is according to formula (XXXVI), wherein R³ is methoxy, R¹is methyl, R² is H, and R⁴ is H. In an exemplary embodiment, thecompound is according to formula (XXXVI), wherein R³ is F, R¹ is methyl,R² is F, and R⁴ is H. In an exemplary embodiment, the compound isaccording to formula (XXXVI), wherein R³ is OCHF₂, R¹ is methyl, R² isH, and R⁴ is H. In an exemplary embodiment, the compound is according toformula (XXXVI), wherein R³ is methoxy, R¹ is methyl, R² is H, and R⁴ isH. In an exemplary embodiment, the compound is according to formula(XXXVI), wherein R³ is ethoxy, R¹ is methyl, R² is H, and R⁴ is H. In anexemplary embodiment, the compound is according to formula (XXXVI),wherein R³ is OCF₃, R¹ is methyl, R² is H, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R³ isCl, R¹ is methyl, R² is H, and R⁴ is H. In an exemplary embodiment, thecompound is according to formula (XXXVI), wherein R³ is F, R¹ is methyl,R² is H, and R⁴ is F. In an exemplary embodiment, the compound isaccording to formula (XXXVI), wherein R², R³, and R⁴ are as describedherein, and R¹ is ethyl. In an exemplary embodiment, the compound isaccording to formula (XXXVI), wherein R² and R³ are as described herein,R¹ is ethyl, and R⁴ is H. In an exemplary embodiment, the compound isaccording to formula (XXXVI), wherein R² is as described herein, R¹ isethyl, R³ is H, and R⁴ is H. In an exemplary embodiment, the compound isaccording to formula (XXXVI), wherein R³ is as described herein, R¹ isethyl, R² is H, and R⁴ is H. In an exemplary embodiment, the compound isaccording to formula (XXXVI), wherein R³ is methyl, R¹ is ethyl, R² isH, and R⁴ is H. In an exemplary embodiment, the compound is according toformula (XXXVI), wherein R³ is methoxy, R¹ is ethyl, R² is H, and R⁴ isH. In an exemplary embodiment, the compound is according to formula(XXXVI), wherein R³ is F, R¹ is ethyl, R² is F, and R⁴ is H. In anexemplary embodiment, the compound is according to formula (XXXVI),wherein R³ is OCHF₂, R¹ is ethyl, R² is H, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVI), wherein R³ ismethoxy, R¹ is ethyl, R² is H, and R⁴ is H. In an exemplary embodiment,the compound is according to formula (XXXVI), wherein R³ is ethoxy, R¹is ethyl, R² is H, and R⁴ is H. In an exemplary embodiment, the compoundis according to formula (XXXVI), wherein R³ is OCF₃, R¹ is ethyl, R² isH, and R⁴ is H. In an exemplary embodiment, the compound is according toformula (XXXVI), wherein R³ is Cl, R¹ is ethyl, R² is H, and R⁴ is H. Inan exemplary embodiment, the compound is according to formula (XXXVI),wherein R³ is F, R¹ is ethyl, R² is H, and R⁴ is F.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXXVII):

wherein R¹, R², R³, and R⁴ are as described herein. In an exemplaryembodiment, the compound is according to formula (XXXVII), wherein R¹,R², and R³ are as described herein, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVII), wherein R¹and R² are as described herein, R³ is H and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVII), wherein R¹ isas described herein, R² is H, R³ is H, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVII), wherein R¹and R³ are as described herein, R² is H and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVII), wherein R²,R³, and R⁴ are as described herein, and R¹ is methyl. In an exemplaryembodiment, the compound is according to formula (XXXVII), wherein R²,R³, and R⁴ are as described herein, and R¹ is methyl. In an exemplaryembodiment, the compound is according to formula (XXXVII), wherein R²and R³ are as described herein, R¹ is methyl, and R⁴ is H. In anexemplary embodiment, the compound is according to formula (XXXVII),wherein R² is as described herein, R¹ is methyl, R³ is H, and R⁴ is H.In an exemplary embodiment, the compound is according to formula(XXXVII), wherein R³ is as described herein, R¹ is methyl, R² is H, andR⁴ is H. In an exemplary embodiment, the compound is according toformula (XXXVII), wherein R³ is methyl, R¹ is methyl, R² is H, and R⁴ isH. In an exemplary embodiment, the compound is according to formula(XXXVII), wherein R³ is methoxy, R¹ is methyl, R² is H, and R⁴ is H. Inan exemplary embodiment, the compound is according to formula (XXXVII),wherein R³ is F, R¹ is methyl, R² is F, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVII), wherein R³ isOCHF₂, R¹ is methyl, R² is H, and R⁴ is H. In an exemplary embodiment,the compound is according to formula (XXXVII), wherein R³ is methoxy, R¹is methyl, R² is H, and R⁴ is H. In an exemplary embodiment, thecompound is according to formula (XXXVII), wherein R³ is ethoxy, R¹ ismethyl, R² is H, and R⁴ is H. In an exemplary embodiment, the compoundis according to formula (XXXVII), wherein R³ is OCF₃, R¹ is methyl, R²is H, and R⁴ is H. In an exemplary embodiment, the compound is accordingto formula (XXXVII), wherein R³ is Cl, R¹ is methyl, R² is H, and R⁴ isH. In an exemplary embodiment, the compound is according to formula(XXXVII), wherein R³ is F, R¹ is methyl, R² is H, and R⁴ is F. In anexemplary embodiment, the compound is according to formula (XXXVII),wherein R², R³, and R⁴ are as described herein, and R¹ is ethyl. In anexemplary embodiment, the compound is according to formula (XXXVII),wherein R² and R³ are as described herein, R¹ is ethyl, and R⁴ is H. Inan exemplary embodiment, the compound is according to formula (XXXVII),wherein R² is as described herein, R¹ is ethyl, R³ is H, and R⁴ is H. Inan exemplary embodiment, the compound is according to formula (XXXVII),wherein R³ is as described herein, R¹ is ethyl, R² is H, and R⁴ is H. Inan exemplary embodiment, the compound is according to formula (XXXVII),wherein R³ is methyl, R¹ is ethyl, R² is H, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVII), wherein R³ ismethoxy, R¹ is ethyl, R² is H, and R⁴ is H. In an exemplary embodiment,the compound is according to formula (XXXVII), wherein R³ is F, R¹ isethyl, R² is F, and R⁴ is H. In an exemplary embodiment, the compound isaccording to formula (XXXVII), wherein R³ is OCHF₂, R¹ is ethyl, R² isH, and R⁴ is H. In an exemplary embodiment, the compound is according toformula (XXXVII), wherein R³ is methoxy, R¹ is ethyl, R² is H, and R⁴ isH. In an exemplary embodiment, the compound is according to formula(XXXVII), wherein R³ is ethoxy, R¹ is ethyl, R² is H, and R⁴ is H. In anexemplary embodiment, the compound is according to formula (XXXVII),wherein R³ is OCF₃, R¹ is ethyl, R² is H, and R⁴ is H. In an exemplaryembodiment, the compound is according to formula (XXXVII), wherein R³ isCl, R¹ is ethyl, R² is H, and R⁴ is H. In an exemplary embodiment, thecompound is according to formula (XXXVII), wherein R³ is F, R¹ is ethyl,R² is H, and R⁴ is F.

In another aspect, the invention provides a compound, or a salt or ahydrate or a solvate thereof, having a structure according to formula(XXXVIII):

wherein Y, Z, R¹, R³, R⁵, and R⁶ are as described herein. In anexemplary embodiment, the compound is according to formula (XXXVIII),wherein Y is C(O), Z is O or NH, R¹ is ethyl, R³ is F, and R⁵ and R⁶ areas described herein. In an exemplary embodiment, the compound isaccording to formula (XXXVIII), wherein Y is C(O), Z is O or NH, R¹ ismethyl, R³ is F, and R⁵ and R⁶ are as described herein. In an exemplaryembodiment, the compound is according to formula (XXXVIII), wherein Y isC(O), Z is O or NH, R³ is F, and R¹, R⁵ and R⁶ are as described herein.

In an exemplary embodiment, the compound is according to a formuladescribed herein, wherein this structure

is selected from the group in the following table

In an exemplary embodiment, alkyl is linear alkyl. In another exemplaryembodiment, alkyl is branched alkyl.

In an exemplary embodiment, heteroalkyl is linear heteroalkyl. Inanother exemplary embodiment, heteroalkyl is branched heteroalkyl.

In an exemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof, or a combination thereof.In an exemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or asalt thereof. In an exemplary embodiment, the salt is a pharmaceuticallyacceptable salt. In an exemplary embodiment, the invention provides acompound described herein, or a hydrate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or asolvate thereof. In an exemplary embodiment, the invention provides acompound described herein, or a prodrug thereof. In an exemplaryembodiment, the invention provides a salt of a compound describedherein. In an exemplary embodiment, the invention provides apharmaceutically acceptable salt of a compound described herein. In anexemplary embodiment, the invention provides a hydrate of a compounddescribed herein. In an exemplary embodiment, the invention provides asolvate of a compound described herein. In an exemplary embodiment, theinvention provides a prodrug of a compound described herein.

III.b) Combinations Comprising Additional Therapeutic Agents

The compounds of the invention may also be used in combination withadditional therapeutic agents. The invention thus provides, in a furtheraspect, a combination comprising a compound of the invention togetherwith at least one additional therapeutic agent. In an exemplaryembodiment, the combination comprises a compound described herein or apharmaceutically acceptable salt thereof together with at least oneadditional therapeutic agent. In an exemplary embodiment, the additionaltherapeutic agent is a compound of the invention. In an exemplaryembodiment, the combination comprises: a) a compound of the inventionand b) a first additional therapeutic agent. In an exemplary embodiment,the combination comprises: a) a compound of the invention; b) a firstadditional therapeutic agent; and c) a second additional therapeuticagent. In an exemplary embodiment, the combination comprises: a) acompound of the invention; b) a first additional therapeutic agent; c) asecond additional therapeutic agent; and d) a third additionaltherapeutic agent. In an exemplary embodiment, the combinationcomprises: a) a compound of the invention according to a formulaprovided herein and b) a first additional therapeutic agent. In anexemplary embodiment, the combination comprises: a) a compound of theinvention according to a formula provided herein; b) a first additionaltherapeutic agent; and c) a second additional therapeutic agent.

In an exemplary embodiment, an additional therapeutic agent is achemotherapeutic and/or radiation treatment. In an exemplary embodiment,an additional therapeutic agent is radiation treatment. In an exemplaryembodiment, an additional therapeutic agent is an antitumor agent. In anexemplary embodiment, an additional therapeutic agent is an antitumoralkylating agent, an antitumor antimetabolite, an antitumor antibiotic,a plant-derived antitumor agent, an antitumor organoplatinum compound,an antitumor campthotecin derivative, an antitumor tyrosine kinaseinhibitor, a checkpoint inhibitor, a monoclonal antibody, anangiogenesis inhibitor, an immunotherapy, an interferon, or a biologicalresponse modifier, or a pharmaceutically acceptable salt thereof.

When a compound of the invention is used in combination with at leastone additional therapeutic agent active against the same disease state,the dose of each compound may differ from that when the compound is usedalone. Appropriate doses will be readily appreciated by those skilled inthe art. It will be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated and the age and the condition of the patient andwill be ultimately at the discretion of the attendant physician.

In an exemplary embodiment, the additional therapeutic agent is usefulin treating cancer. In an exemplary embodiment, the additionaltherapeutic agent is cisplatin. In an exemplary embodiment, theadditional therapeutic agent is paclitaxel.

The individual components of such combinations may be administeredeither simultaneously or sequentially in a unit dosage form. The unitdosage form may be a single or multiple unit dosage forms. In anexemplary embodiment, the invention provides a combination in a singleunit dosage form. An example of a single unit dosage form is a capsulewherein both the compound of the invention and the additionaltherapeutic agent are contained within the same capsule. In an exemplaryembodiment, the invention provides a combination in a two unit dosageform. An example of a two unit dosage form is a first capsule whichcontains the compound of the invention and a second capsule whichcontains the additional therapeutic agent. Thus the term ‘single unit’or ‘two unit’ or ‘multiple unit’ refers to the object which the patientingests, not to the interior components of the object. Appropriate dosesof known therapeutic agents will be readily appreciated by those skilledin the art.

The combinations referred to herein may conveniently be presented foruse in the form of a pharmaceutical formulation. Thus, an exemplaryembodiment of the invention is a pharmaceutical formulation comprisinga) a compound of the invention; b) an additional therapeutic agent andc) a pharmaceutically acceptable excipient. In an exemplary embodiment,the pharmaceutical formulation is a unit dosage form. In an exemplaryembodiment, the pharmaceutical formulation is a single unit dosage form.In an exemplary embodiment, the pharmaceutical formulation is a two unitdosage form. In an exemplary embodiment, the pharmaceutical formulationis a two unit dosage form comprising a first unit dosage form and asecond unit dosage form, wherein the first unit dosage form includes a)a compound of the invention and b) a first pharmaceutically acceptableexcipient; and the second unit dosage form includes c) an additionaltherapeutic agent and d) a second pharmaceutically acceptable excipient.

It is to be understood that the invention covers all combinations ofaspects and/or embodiments, as well as suitable, convenient andpreferred groups described herein.

Compounds described herein can be converted into hydrates and solvatesby methods similar to those described herein.

IV. Methods of Inhibiting PARP and/or Tubulin

The compounds of the invention inhibit one or more proteins, and saidone or more proteins are PARP and/or tubulin, and therefore have thepotential to treat diseases in which these proteins are associated. Thecompounds of the invention inhibit tubulin, and therefore have thepotential to treat diseases in which tubulin is associated. Thecompounds of the invention inhibit PARP, and therefore have thepotential to treat diseases in which PARP is associated. In an exemplaryembodiment, the PARP is PARP1. In an exemplary embodiment, the PARP isPARP2. In an exemplary embodiment, the compounds of the inventioninhibit one or more proteins, and said one or more proteins are PARP1and/or PARP2 and/or tubulin, and therefore have the potential to treatdiseases in which these proteins are associated.

In a further aspect, the invention provides a method of inhibiting PARPand/or tubulin, said method comprising: contacting said PARP and/ortubulin with an effective amount of a compound of the invention, therebyinhibiting said PARP and/or tubulin. In a further aspect, the inventionprovides a method of inhibiting PARP, said method comprising: contactingsaid PARP with an effective amount of a compound of the invention,thereby inhibiting said PARP. In a further aspect, the inventionprovides a method of inhibiting tubulin, said method comprising:contacting said tubulin with an effective amount of a compound of theinvention, thereby inhibiting said tubulin. In a further aspect, theinvention provides a method of inhibiting PARP1 and/or PARP2 and/ortubulin, said method comprising: contacting said PARP1 and/or PARP2and/or tubulin with an effective amount of a compound of the invention,thereby inhibiting said PARP1 and/or PARP2 and/or tubulin. In anexemplary embodiment, the one or more proteins is one protein which isPARP1. In an exemplary embodiment, the one or more proteins is oneprotein which is PARP2. In an exemplary embodiment, the one or moreproteins is one protein which is tubulin. In an exemplary embodiment,the one or more proteins are two proteins which are PARP1 and tubulin.In an exemplary embodiment, the one or more proteins are two proteinswhich are PARP2 and tubulin. In an exemplary embodiment, the one or moreproteins are two proteins which are PARP1 and PARP2. In an exemplaryembodiment, the invention provides a method of inhibiting PARP1 and/orPARP2 and/or tubulin, comprising: contacting said PARP1 and/or PARP2and/or tubulin with an effective amount of the compound of theinvention, thereby inhibiting said PARP1 and/or PARP2 and/or tubulin.

V. Methods of Treating Disease

The compounds of the invention exhibit potency against disease, such ascancer, and therefore have the potential to achieve therapeutic efficacyin the animals described herein.

In an exemplary embodiment, the invention provides a method of treatinga disease. The method includes administering to the animal atherapeutically effective amount of the compound of the invention,sufficient to treat the disease. In an exemplary embodiment, theinvention provides a method of treating a disease in an animalcomprising administering to the animal a therapeutically effectiveamount of the compound of the invention, wherein the animal is in needof treatment, sufficient to treat the disease. In another aspect, theinvention provides a method of treating a disease in an animalcomprising administering to the animal a therapeutically effectiveamount of the compound of the invention, wherein the animal is nototherwise in need of treatment with the compound of the invention,sufficient to treat the disease. In an exemplary embodiment, the diseaseis a tumor. In an exemplary embodiment, the disease is a tumor, and thetumor is benign, or non-cancerous. In an exemplary embodiment, thedisease is a tumor, and the tumor is malignant, or cancerous. In anexemplary embodiment, the disease is a tumor, and the tumor is benign(non-cancerous). In an exemplary embodiment, the disease is cancer. Inan exemplary embodiment, the disease is cancer. In an exemplaryembodiment, the term “cancer” defines any malignant cancerous growth. Inan exemplary embodiment, the disease is a sarcoma, adrenal corticalcancer, anal cancer, aplastic anemia, bile duct cancer, bladder cancer,bone cancer, bone metastasis, a central nervous system (CNS) cancer, aperipheral nervous system (PNS) cancer, Castleman's Disease, cervicalcancer, colon cancer, rectum cancer, endometrial cancer, esophaguscancer, Ewing's family of tumors (e.g. Ewing's sarcoma), eye cancer,gallbladder cancer, a gastrointestinal carcinoid tumor, agastrointestinal stromal tumor, gestational trophoblastic disease, hairycell leukemia, Hodgkin's disease, kidney cancer, laryngeal cancer, ahypopharyngeal cancer, acute lymphocytic leukemia, acute myeloidleukemia, children's leukemia, chronic lymphocytic leukemia, chronicmyeloid leukemia, liver cancer, lung cancer, a lung carcinoid tumor,malignant mesothelioma, multiple myeloma, myelodysplastic syndrome,myeloproliferative disorders, a nasal cavity cancer, a paranasal cancer,nasopharyngeal cancer, neuroblastoma, an oral cavity cancer, anoropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer,penile cancer, pituitary tumor, prostate cancer, retinoblastoma,rhabdomyosarcoma, salivary gland cancer, an adult soft tissue cancer,melanoma skin cancer, non-melanoma skin cancer, stomach cancer,testicular cancer, thymus cancer, thyroid cancer, uterine cancer (e.g.uterine sarcoma), vaginal cancer, vulvar cancer, or Waldenstrom'smacroglobulinemia.

In an exemplary embodiment, the disease is a cancer of the blood, suchas leukemia, cancer of the skin, such as melanoma, cancer of the colon,cancer of the lung, cancer of the ovary, cancer of the uterus, cancer ofthe breast, cancer of the prostate, cancer of the pancreas. In anexemplary embodiment, the disease is a cancer of the central nervoussystem, or a cancer of the renal system. In an exemplary embodiment, thedisease is a soft tissue cancer. In an exemplary embodiment, the diseaseis multiple myeloma. In an exemplary embodiment, the cancer is ovariancancer. In an exemplary embodiment, the cancer is uterine cancer. In anexemplary embodiment, the cancer is pancreatic cancer. In an exemplaryembodiment, the cancer is lung cancer. In an exemplary embodiment, thecancer is brain cancer. In an exemplary embodiment, the cancer is skincancer. In some embodiments, the cancer is colon cancer. In an exemplaryembodiment, the cancer is derived from cancer stem cells.

In an exemplary embodiment, the cancer is breast cancer. In an exemplaryembodiment, the breast cancer is negative for one or more of EstrogenReceptor (ER), Progesterone Receptor (PR), or Human Epidermal GrowthFactor Receptor 2 (HER2). In an exemplary embodiment, the breast canceris negative for one or more of ER, PR or HER2; and wherein the breastcancer is positive for one or more of ER, PR or HER2. In an exemplaryembodiment, the breast cancer is negative for two of ER, PR or HER2. Inan exemplary embodiment, the breast cancer is ER negative andPR-negative.

In an exemplary embodiment, the breast cancer is ER-negative andHER2-negative. In an exemplary embodiment, the breast cancer isPR-negative and HER2-negative. In an exemplary embodiment, the breastcancer is an ER-negative breast cancer. In an exemplary embodiment, thebreast cancer is an HER2-negative breast cancer.

In an exemplary embodiment, a compound of the invention treats a diseasein an animal, by inhibiting tubulin polymerization and/or PARP activity.The present invention thus provides a method for treating a disease byinhibiting either or both tubulin polymerization and PARP activitycomprising the step of administering compounds of the invention to apatient in need thereof.

In an exemplary embodiment, a compound of the invention is used at anearly stage of a disease, or before early onset, or after significantprogression, including metastasis in case of cancer. The term“treatment” or “treating” applied to tumor can refer to a reduction ofthe burden in a patient, such as a reduction in cell proliferation rate,a destruction of diseased proliferative cells, a reduction of tumor massor tumor size, a delaying of tumor progression, or a complete tumorsuppression.

In an exemplary embodiment, a compound of the invention can be used intreatment of cancers deficient in Homologous Recombination (HR)dependent DNA double strand repair (DSB), which consist or comprise oneor more cancer cells which have a reduced or abrogated ability to repairDNA DSBs through that pathway.

In an exemplary embodiment, a compound of the invention can be used inany disease state for which either or both tubulin polymerisation andPARP play a role.

In an exemplary embodiment, the disease is a bacterial infection. In anexemplary embodiment, the disease is a bacterial ulcer infection. In anexemplary embodiment, the disease is a viral infection. In an exemplaryembodiment, the disease is a herpes simplex infection. In an exemplaryembodiment, the disease is an Acquired Immune Deficiency Syndrome (AIDS)infection. In an exemplary embodiment, the disease is a protozoalinfection. In an exemplary embodiment, the disease is a flagellatedparasite infection. In an exemplary embodiment, the disease is a Chagas'disease. In an exemplary embodiment, the disease is Leishmania.

In an exemplary embodiment, the disease is vascular neointimalhyperplasia.

In an exemplary embodiment, the invention provides a use of a compoundof a invention in the manufacture of a medicament for the treatment of adisease described herein.

In an exemplary embodiment, a compound of the invention may be dosed atintervals of minutes, hours, days, weeks, months or years orcontinuously over any one of these periods. Suitable dosage amounts anddosing regimens can be determined by the attending physician and maydepend on the particular condition being treated, the severity of thecondition as well as the general age, health and weight of the subject.

In an exemplary embodiment, a compound of the invention may beadministered in a single dose or a series of doses.

In another exemplary embodiment, the animal is a eukaryote. In anotherexemplary embodiment, the animal is a vertebrate animal. In anotherexemplary embodiment, the animal is a mammal. In another exemplaryembodiment, the animal is a rodent. In another exemplary embodiment, theanimal is a mouse. In another exemplary embodiment, the animal is ahorse. In another exemplary embodiment, the animal is a primate or asimian. In another exemplary embodiment, the animal is a monkey or anape. In another exemplary embodiment, the animal is a human or a farmanimal or a companion animal. In another exemplary embodiment, theanimal is a human. In another exemplary embodiment, the animal is a goator pig or sheep or horse or cow or bull. In another exemplaryembodiment, the animal is a cat. In another exemplary embodiment, theanimal is a dog. In another exemplary embodiment, the animal is arabbit.

The compounds of the invention may be administered to a subject by anyconvenient route of administration, whether systemically/peripherally orat the site of desired action, including but not limited to oral e.g.tablets, chewable tablets or capsules); topical (e.g. transdermal,intranasal, ocular, buccal, and sublingual); pulmonary (e.g. inhalationor insufflation therapy using, e.g. an aerosol, e.g. through mouth ornose); rectal; vaginal, parenteral, for example, by injection, includingsubcutaneous, intradermal, intramuscular, intravenous, intraarterial,intracardiac, intrathecal, intraspinal, intreacapsular, subcupsular,intraorbital, intraperitoneal, intratracheal, subcuticular,intraarticular, subarachnoid, and intrasternal; by implant of a depot,for example, subcutaneously or intramuscularly.

In an exemplary embodiment, the disease is treated through oraladministration of the compound of the invention. In an exemplaryembodiment, the disease is treated through intravenous administration ofthe compound of the invention. In an exemplary embodiment, the diseaseis treated through topical administration of the compound of theinvention. In an exemplary embodiment, the disease is treated throughintraperitoneal administration of the compound of the invention. In anexemplary embodiment, the compound is administered in a topicallyeffective amount. In an exemplary embodiment, the compound isadministered in a cosmetically effective amount. In an exemplaryembodiment, the pharmaceutical formulation is administered in an orallyeffective amount.

VI. Pharmaceutical Formulations

In another aspect, the invention is a pharmaceutical formulation whichincludes: (a) a pharmaceutically acceptable excipient; and (b) acompound of the invention. In another aspect, the pharmaceuticalformulation includes: (a) a pharmaceutically acceptable excipient; and(b) a compound according to a formula described herein. In anotheraspect, the pharmaceutical formulation includes: (a) a pharmaceuticallyacceptable excipient; and (b) a compound described herein, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. Inanother aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a compound describedherein, or a salt, hydrate or solvate thereof, or a combination thereof.In another aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a compound describedherein, or a salt, hydrate or solvate thereof. In another aspect, thepharmaceutical formulation includes: (a) a pharmaceutically acceptableexcipient; and (b) a salt of a compound described herein. In anexemplary embodiment, the salt is a pharmaceutically acceptable salt. Inanother aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a prodrug of a compounddescribed herein. In another exemplary embodiment, the pharmaceuticalformulation includes: (a) a pharmaceutically acceptable excipient; and(b) a compound described herein. In an exemplary embodiment, thepharmaceutical formulation is a unit dosage form. In an exemplaryembodiment, the pharmaceutical formulation is a single unit dosage form.

The pharmaceutical formulations of the invention can take a variety offorms adapted to the chosen route of administration. Those skilled inthe art will recognize various synthetic methodologies that may beemployed to prepare non-toxic pharmaceutical formulations incorporatingthe compounds described herein. Those skilled in the art will recognizea wide variety of non-toxic pharmaceutically acceptable solvents thatmay be used to prepare solvates of the compounds of the invention, suchas water, ethanol, propylene glycol, mineral oil, vegetable oil anddimethylsulfoxide (DMSO).

The pharmaceutical formulation of the invention may be administeredorally, topically, intraperitoneally, parenterally, by inhalation orspray or rectally in unit dosage forms containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. It isfurther understood that the best method of administration may be acombination of methods. Oral administration in the form of a pill,capsule, elixir, syrup, lozenge, troche, or the like is particularlypreferred. The term parenteral as used herein includes subcutaneousinjections, intradermal, intravascular (e.g., intravenous),intramuscular, spinal, intrathecal injection or like injection orinfusion techniques. In an exemplary embodiment, the pharmaceuticalformulation is administered orally. In an exemplary embodiment, thepharmaceutical formulation is administered intravenously. In anexemplary embodiment, the pharmaceutical formulation is administered ina topically effective dose. In an exemplary embodiment, thepharmaceutical formulation is administered in a cosmetically effectivedose. In an exemplary embodiment, the pharmaceutical formulation isadministered in an orally effective dose.

The pharmaceutical formulations containing compounds of the inventionare preferably in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known in the art for the manufacture of pharmaceuticalformulations, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;and dispersing or wetting agents, which may be a naturally-occurringphosphatide, for example, lecithin, or condensation products of analkylene oxide with fatty acids, for example polyoxyethylene stearate,or condensation products of ethylene oxide with long chain aliphaticalcohols, for example heptadecaethyleneoxycetanol, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand a hexitol such as polyoxyethylene sorbitol monooleate, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example polyethylene sorbitanmonooleate. The aqueous suspensions may also contain one or morepreservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one ormore coloring agents, one or more flavoring agents, and one or moresweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical formulations of the invention may also be in the form ofoil-in-water emulsions and water-in-oil emulsions. The oily phase may bea vegetable oil, for example olive oil or arachis oil, or a mineral oil,for example liquid paraffin or mixtures of these. Suitable emulsifyingagents may be naturally-occurring gums, for example gum acacia or gumtragacanth; naturally-occurring phosphatides, for example soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol; anhydrides, for example sorbitan monooleate; and condensationproducts of the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents. The pharmaceutical formulations may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents, which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The composition of the invention may also be administered in the form ofsuppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Alternatively, the compositions can be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

For administration to non-human animals, the composition containing thetherapeutic compound may be added to the animal's feed or drinkingwater. Also, it will be convenient to formulate animal feed and drinkingwater products so that the animal takes in an appropriate quantity ofthe compound in its diet. It will further be convenient to present thecompound in a composition as a premix for addition to the feed ordrinking water. The composition can also added as a food or drinksupplement for humans.

Dosage levels of the order of from about 5 mg to about 250 mg perkilogram of body weight per day and more preferably from about 25 mg toabout 150 mg per kilogram of body weight per day, are useful in thetreatment of the above-indicated conditions. The amount of activeingredient that may be combined with the carrier materials to produce aunit dosage form will vary depending upon the condition being treatedand the particular mode of administration. Unit dosage forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily or less is preferred. It will beunderstood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration and rate ofexcretion, drug combination and the severity of the particular diseaseundergoing therapy.

In an exemplary embodiment, the unit dosage form contains from about 1mg to about 800 mg of a compound of the invention. In an exemplaryembodiment, the unit dosage form contains from about 1 mg to about 500mg of an active ingredient. In an exemplary embodiment, the unit dosageform contains from about 100 mg to about 800 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 200 mg to about 500 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 500 mg toabout 800 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 1 mg to about 100 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 10 mg to about 100 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 50 mg to about 100 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 25 mg toabout 75 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 40 mg to about 60 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 75 mg to about 200 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 1 mg to about 5 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 10 mg toabout 25 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 50 mg to about 350 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 200 mg to about 400 mg of a compound of theinvention.

In an exemplary embodiment, the daily dosage contains from about 1 mg toabout 800 mg of a compound of the invention. In an exemplary embodiment,the daily dosage contains from about 1 mg to about 500 mg of an activeingredient. In an exemplary embodiment, the daily dosage contains fromabout 100 mg to about 800 mg of a compound of the invention. In anexemplary embodiment, the daily dosage contains from about 200 mg toabout 500 mg of a compound of the invention. In an exemplary embodiment,the daily dosage contains from about 500 mg to about 800 mg of acompound of the invention. In an exemplary embodiment, the daily dosagecontains from about 1 mg to about 100 mg of a compound of the invention.In an exemplary embodiment, the daily dosage contains from about 10 mgto about 100 mg of a compound of the invention. In an exemplaryembodiment, the daily dosage contains from about 50 mg to about 100 mgof a compound of the invention. In an exemplary embodiment, the dailydosage contains from about 75 mg to about 200 mg of a compound of theinvention. In an exemplary embodiment, the daily dosage contains fromabout 1 mg to about 5 mg of a compound of the invention. In an exemplaryembodiment, the daily dosage contains from about 10 mg to about 25 mg ofa compound of the invention. In an exemplary embodiment, the dailydosage contains from about 50 mg to about 350 mg of a compound of theinvention. In an exemplary embodiment, the daily dosage contains fromabout 200 mg to about 400 mg of a compound of the invention.

Preferred compounds of the invention will have desirable pharmacologicalproperties that include, but are not limited to, oral bioavailability,low toxicity, low serum protein binding and desirable in vitro and invivo half-lives. Penetration of the blood brain barrier for compoundsused to treat CNS disorders is necessary, while low brain levels ofcompounds used to treat peripheral disorders are often preferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocytes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of laboratory animalsthat receive the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcova, et al. (Journal ofChromatography B (1996) volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lives of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

The amount of the composition required for use in treatment will varynot only with the particular compound selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the patient and will ultimately be at the discretion ofthe attendant physician or clinician.

VI. a) Testing

Preferred compounds for use in the pharmaceutical formulations describedherein will have certain pharmacological properties. Such propertiesinclude, but are not limited to, low toxicity, low serum protein bindingand desirable in vitro and in vivo half-lives. Assays may be used topredict these desirable pharmacological properties. Assays used topredict bioavailability include transport across human intestinal cellmonolayers, including Caco-2 cell monolayers. Serum protein binding maybe predicted from albumin binding assays. Such assays are described in areview by Oravcova et al. (1996, J. Chromat. B677: 1-27). Compoundhalf-life is inversely proportional to the frequency of dosage of acompound. In vitro half-lives of compounds may be predicted from assaysof microsomal half-life as described by Kuhnz and Gleschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD50 (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio between LD₅₀and ED₅₀. Compounds that exhibit high therapeutic indices are preferred.The data obtained from these cell culture assays and animal studies canbe used in formulating a range of dosage for use in humans. The dosageof such compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage can vary within this range depending upon the unit dosage formemployed and the route of administration utilized. The exactformulation, route of administration and dosage can be chosen by theindividual physician in view of the patient's condition. (See, e.g.Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch.1, p. 1).

VI. b) Administration

For any compound used in the method of the invention, thetherapeutically effective dose can be estimated initially from cellculture assays, as disclosed herein. For example, a dose can beformulated in animal models to achieve a circulating concentration rangethat includes the EC₅₀ (effective dose for 50% increase) as determinedin cell culture, i.e., the concentration of the test compound whichachieves a half-maximal inhibition of infected cell growth. Suchinformation can be used to more accurately determine useful doses inhumans.

In general, the compounds prepared by the methods, and from theintermediates, described herein will be administered in atherapeutically or cosmetically effective amount by any of the acceptedmodes of administration for agents that serve similar utilities. It willbe understood, however, that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, and rate ofexcretion, drug combination, the severity of the particular diseaseundergoing therapy and the judgment of the prescribing physician. Thedrug can be administered from once or twice a day, or up to 3 or 4 timesa day.

Dosage amount and interval can be adjusted individually to provideplasma levels of the active moiety that are sufficient to maintaininfected cell growth inhibitory effects. Usual patient dosages forsystemic administration range from 0.1 to 1000 mg/day, preferably, 1-500mg/day, more preferably 10-200 mg/day, even more preferably 100-200mg/day. Stated in terms of patient body surface areas, usual dosagesrange from 50-91 mg/m²/day.

The amount of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-10 wt %of the drug based on the total formulation, with the balance being oneor more suitable pharmaceutical excipients. Preferably, the compound ispresent at a level of about 0.1-3.0 wt %, more preferably, about 1.0 wt%.

The invention is further illustrated by the Examples that follow. TheExamples are not intended to define or limit the scope of the invention.

EXAMPLES

The following Examples illustrate the synthesis of representativecompounds used in the invention and the following Reference Examplesillustrate the synthesis of intermediates in their preparation. Theseexamples are not intended, nor are they to be construed, as limiting thescope of the invention. It will be clear that the invention may bepracticed otherwise than as particularly described herein. Numerousmodifications and variations of the invention are possible in view ofthe teachings herein and, therefore, are within the scope of theinvention.

In the examples below, unless otherwise indicated, all temperatures areset forth in degrees Celsius and all parts and percentages are byweight. Reagents may be purchased from commercial suppliers, such asSigma-Aldrich Chemical Company, and may be used without furtherpurification unless otherwise indicated. Reagents may also be preparedfollowing standard literature procedures known to those skilled in theart. Solvents may be purchased from Sigma-Aldrich in Sure-Seal bottlesand used as received. All solvents may be purified using standardmethods known to those skilled in the art, unless otherwise indicated.The reactions set forth below were run generally at ambient temperature,unless otherwise indicated. The reaction vessels were fitted with rubbersepta for introduction of substrates and reagents via syringe.Analytical thin layer chromatography (TLC) was performed usingglass-backed silica gel pre-coated plates (Analtech TLC Uniplates™ withfluorescent indicator) and eluted with appropriate solvent ratios (v/v).Reactions were assayed by TLC or LC/MS, and terminated as judged by theconsumption of starting material. Visualization of the TLC plates wasdone with UV light (254 nm wavelength) or with an appropriate TLCvisualizing solvent, such as basic aqueous KMnO4 solution, ninhydrin,cerium molybdate, or phosphomolybdic acid, activated with heat. Flashcolumn chromatography (W. C. Still et al., J. Org. Chem., 43, 1978,2923-2925) was performed using Biotage Isolera Prime automated flashpurification system (220 and 254 nm wavelength) with ZIPSphere-spherical Silica or KP Silica cartridges or various preparativeHPLC systems. The compound structures in the examples below wereconfirmed by one or more of the following methods: proton magneticresonance spectroscopy, mass spectrometry, and melting point. Protonmagnetic resonance (1HNMR) spectra were recorded using an NMRspectrometers operating at 300, 400 or 500 MHz field strength. Chemicalshifts are reported in the form of delta (6) values given in parts permillion (ppm) relative to an internal standard, such astetramethylsilane (TMS). Alternatively, 1HNMR spectra were referenced tosignals from residual protons in deuterated solvents as follows:CDCl₃=7.25 ppm; DMSO-d₆=2.49 ppm; CD₃OD=3.30 ppm. Peak multiplicitiesare designated as follows: s, singlet; d, doublet; dd, doublet ofdoublets; t, triplet; dt, doublet of triplets; q, quartet; br,broadened; and m, multiplet. Coupling constants are given in Hertz (Hz).Mass spectrometric (MS) data were obtained using a mass spectrometerwith APCI or ESI ionization.

Starting materials used were either available from commercial sources orprepared according to literature procedures and had experimental data inaccordance with those reported.

Synthesis of Compounds of the Invention

Scheme 1 depicts the general synthetic routes for compounds of theinvention and is not intended to be limiting. Specific examples aredescribed subsequently to this general synthetic description. In thegeneralizations below, specific reaction conditions or details, forexample, added reagents, catalysts, solvents, reaction temperature, andthe like are not described. The general routes depicted in conjunctionwith the specific examples provided contain sufficient information toallow one of ordinary skill in the art to synthesize compounds of theinvention.

A number of methods may be available for the synthesis of compoundsrepresented by formula A-3 and A-4; most of them involve the cyclizationof ortho-substituted arylaldehydes, followed by C-3 alkylation,condensation of 3-bromo-pthalides with aldehydes, the Wittig-Hornerreaction of phthalide-3-phosphonate esters (A-1) with aldehyde s (A-2)or reacting phthalic anhydrides with phenylacetic acids. (SCHEME A).

One of the most attractive methods for the synthesis of3-isobenzofurane-1-ones (A-3) is a copper (I) mediated tandemSonogashira coupling and intramolecular 5-exo-dig cyclization reaction.For example, reaction of 2-iodobenzoic acid (A-5a) and phenyl acetylenes(A-6) in the presence of a copper catalyst (copper(I) bromide, copper(I)iodide) and organic (trimethylamine, Hunig's base) or inorganic(potassium carbonate, cesium carbonate) bases in an appropriate solvent(dimethyl sulfoxide, N,N-dimethyl formamide) afford A-3 in excellentyield. 2-Bromobenzoic acid (A-5b) and terminal alkyne (A-6) may also beused in similar fashion. Electron withdrawing groups such as halogensand/or a pyridyl ring in combination with the carboxylic acid moiety inthe A-5 component increase the reactivity of the C-Halogen bondproducing phthalides in good yields. Electron-donating groups (methyl,methoxy, tert-butyl) in both, the benzoic acid and the alkyne componentsdecrease the reactivity of the alkyne moiety as well as the reactivityof the C-Halogen bond, resulting in lower yields (SCHEME B.).

LITERATURE

-   1. Synthesis of dimethyl phthalide-3-phosphonates and their use in    the regiospecific synthesis of 3-ylidenephthalides; Elio Napolitano,    Guido Spinelli, Rita Fiaschi, Antonio Marsili; Synthesis, 1985,    38-40.-   2. Regioselective One-Pot Synthesis of Isocoumarins and Phthalides    from 2-Iodobenzoic acids and Alkynes by Temperature Control; Manian    Rajesh Kumar, Francis Mariaraj Irudayanathan, Joong Ho Moon, and    Sunwoo Lee; Adv. Synth. Catal., 2013, 355, 3221-3230.-   3. Pd-free Sonogashira coupling: one pot synthesis of phthalide via    domino Sonogashira coupling and 5-exo-dig cyclization; Shubhendu    Dhara, Raju Singha, Munmun Ghosh, Atiur Ahmed, Yasin Nuree, Anuvab    Das and Jayanta K. Ray; RSC Adv., 2014, 4, 42604-42607.

For the synthesis of the 3-benzylidene-isoindolin-1-one scaffold,represented by formula A-9, a highly efficient copper-mediated tandemoxidative C(sp2)-H/C(sp)-H cross-coupling and intramolecular annulationreaction of arenes with terminal alkynes (A-6) has been developed. Inthis oxidative coupling process, copper(II)acetate acts as both thepromoter and the terminal oxidant, and 8-aminoquinoline as a directingauxiliary (A-8a). This synthetic method tolerates a wide range ofsubstrates and functional groups, proceeds with high chemo-, regio-, andstereoselectivity; it is a simple, readily available, inexpensivereaction system. Isoindolin-1-ones may also be straightforwardlysynthesized from terminal alkynes (A-6) and 8-aminoquinoline benzamides(A-8a) utilizing cobalt(II) catalytic system or form substituted2-aminopyridine 1-oxide amides (A-8b) using nickel(II) catalyst intandem C(sp2)-H alkynylation-annulation reactions. An extension of theabove reaction utilizes optionally substituted alkynyl carboxylic acids(A-7) in copper-catalyzed tandem decarboxylativecross-coupling-cyclization reactions with various substituted aromaticamides (A-8a), bearing electron-withdrawing or electron-donating groups(SCHEME C.).

LITERATURE

-   1. Copper-Mediated Tandem Oxidative C(sp2)-H/C(sp)-H Alkynylation    and Annulation of Arenes with Terminal Alkynes; Jiaxing Dong, Fei    Wang, and Jingsong You; Org. Lett., 2014, 16, 2884-2887.-   2. The facile construction of the phthalazin-1(2H)-one scaffold via    copper-mediated C—H(sp2)/C—H(sp) coupling under mild conditions; Wei    Zhu, Bao Wang, Shengbin Zhou and Hong Liu; Beilstein J. Org. Chem.,    2015, 11, 1624-1631.-   3. Cobalt-Catalyzed Cyclization of Aliphatic Amides and Terminal    Alkynes with Silver-Cocatalyst; Jitan Zhang, Hui Chen, Cong Lin,    Zhanxiang Liu, Chen Wang and Yuhong Zhang; J. Am. Chem. Soc., 2015,    137, 12990-12996.-   4. Ni(II)—Catalyzed C(sp2)-H Alkynylation/Annulation with Terminal    Alkynes under an Oxygen Atmosphere: A One-Pot Approach to    3-Methyleneisoindolin-1-one; Xin-Xiang Zheng, Cong Du, Xue-Mei Zhao,    Xinju Zhu, Jian-Feng Suo, Xin-Qi Hao, Jun-Long Niu and Mao-Ping    Song; J. Org. Chem., 2016, 81, 4002-4011.-   5. Copper(II)/Silver(I)-Catalyzed Sequential Alkynylation and    Annulation of Aliphatic Amides with Alkynyl Carboxylic Acids:    Efficient Synthesis of Pyrrolidones; Jitan Zhang, Danyang Li, Hui    Chen, Binjie Wang, Zhanxiang Liu, and Yuhong Zhang; Adv. Synth.    Catal., 2016, 358, 792-807.

Substituted 4-benzylphthalazin-1(2H)-ones, formula A-10 and A11, may beconveniently synthesized from 3-benzylidene-3H-isobenzofurane-1-ones(A-3 or A-4) or from 3-benzylidene-isoindolin-1-ones (A-9) underhydrazinolysis condition (SCHEME D.).

LITERATURE

-   1. The opening of the lactonic ring of derivatives of phthalide by    hydrazine; Teppemma, T.; Recueil des Travaux Chimiques des Pays-Bas    et de la Belgique, 1923, 42, 30-68.-   2. Derivatives of 3-fluorofluorene by the Pschorr synthesis; Suzuki,    Kazuo, Weisburger, Elizabeth K., Weisburger, John H; Journal of    Organic Chemistry, 1961, 26, 2239-2242.-   3. The facile construction of the phthalazin-1(2H)-one scaffold via    copper-mediated C—H(sp2)/C—H(sp) coupling under mild conditions; Wei    Zhu, Bao Wang, Shengbin Zhou and Hong Liu; Beilstein J. Org. Chem.,    2015, 11, 1624-1631.

Compounds, represented by formula A-11 may also be prepared from anadequately functionalized A-10 in palladium-mediated cross couplingreactions. The heterocyclic ring can be installed directly or may beformed from an appropriate precursor, for example from 2-nitroaniline.Reduction of the 2-nitroaniline intermediate may be carried out under arange of conditions, for example catalytic hydrogenation or hydrogentransfer may be employed using palladium on carbon, platinum oxide orRaney nickel catalysts. Alternatively, iron metal or tin(II) chloridemay also be used as effective reducing agents. Conversion of theresulting phenylenediamine to benzimidazole can be achieved in one step,for example treating the appropriate phenylenediamine with1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea in acetic acid withheating. Alternatively, the conversion may be carried out by treatingthe phenylenediamine intermediate with a substituted isothiocyanate,followed by heating it in the presence of an appropriate carbodiimide.To introduce other carbamates, ureas or amides at the benzimidazole2-position the thiopseudourea reagent of choice may be straightforwardlyprepared. Alternatively, the appropriate 2-amino-benzimidazoleintermediate may also be conveniently functionalized.

Intermediate 1 4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one (I-1.1.)

Method A

STEP 1. To a solution of dimethyl3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (1a) (3.70 g, 15.30 mmol)and 3-bromo-4-fluorobenzaldehyde (2a) (3.10 g, 15.30 mmol) intetrahydrofuran (35 mL) a solution of trimethylamine (2.2 mL, 15.80mmol) in tetrahydrofuran (5 mL) was added dropwise at 0° C. and thereaction mixture was stirred at room temperature overnight. The solventwas concentrated and the residue was partitioned with ethyl acetate (200mL) and 2M aqueous hydrochloric acid (100 mL). The organic layer wasseparated, washed with water (2×100 mL) and brine (2×100 mL), dried overanhydrous sodium sulfate and concentrated. The resulting crude solid wascrystallized from ethyl acetate-hexanes to give(Z)-3-(3-bromo-4-fluorobenzylidene) isobenzofuran-1(3H)-one as withesolid (3a) (3.9 g, 80%). (TLC 10% ethyl acetate in hexanes, Rf.: 0.65).MS (EI) for C₁₅H₈BrFO₂: 319 [M+H].

STEP 2. To a suspension of3-(3-bromo-4-fluorobenzylidene)isobenzofuran-1(3H)-one (3a) (3.80 g,11.90 mmol) in a mixture of water (45 mL) and tetrahydrofuran (15 mL)10N aqueous sodium hydroxide (5.4 mL, 53.55 mmol) was added and thereaction mixture was heated to reflux and stirred until the solid wentinto solution (approximately 1 hour). Upon cooling it to roomtemperature hydrazine monohydrate (64-65 wt %, 9.0 mL, 119.0 mmol) wasadded to the reaction mixture and it was stirred at 90° C. overnight(some precipitate has formed). It was cooled in ice water followed bythe addition of concentrated hydrochloric acid to adjust the pH 4-5(more precipitate formed). The mixture was diluted with ethyl acetate(500 mL) and the organic layer was separated. The aqueous phase waspartitioned with an additional amount of ethyl acetate (300 mL) andseparated. The combined organic phase was washed with water (350 mL) andbrine (2×300 mL), dried over anhydrous sodium sulfate and concentrated.Upon removing the solvent (˜⅔ volume) a white solid product hasprecipitated; it was collected by filtration washed with hexanes anddried in vacuo to give 4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one(I-1.1) (3.6 g, 92%). (TLC 30% ethyl acetate in hexanes, Rf.: 0.50). 1HNMR (300 MHz, d₆-DMSO): 12.57 (s, 1H), 8.26 (d, 1H), 8.02 (d, 1H), 7.89(m, 2H), 7.56 (m, 1H), 7.23 (m, 2H), 4.35 (s, 2H). MS (EI) forC₁₅H₁₀BrFN₂O: 333 [M+H].

Intermediate I-1.2. 4-(3-Bromobenzyl)phthalazin-1(2H)-one was preparedusing 3-bromo benzaldehyde in step 1. MS (EI) for C₁₅H₁₁BrN₂O 315 [M+H].

Intermediate I-1.3. 4-(3-Bromo-4-chlorobenzyl)phthalazin-1 (2H)-one wasprepared using 3-bromo-4-fluorobenzaldehyde in step 1. MS (EI) forC₁₅H₁₀BrClN₂O: 350 [M+H].

Intermediate I-1.4. 4-(3-Bromo-4-methylbenzyl)phthalazin-1 (2H)-one wasprepared using 3-bromo-4-methylbenzaldehyde in step 1. MS (EI) forC₁₆H₁₃BrN₂O: 330 [M+H].

Intermediate I-1.5.4-(3-Bromo-4-(trifluoromethyl)benzyl)phthalazin-1(2H)-one was preparedusing 3-bromo-4-(trifluoromethyl)benzaldehyde in step 1. MS (EI) forC₁₆H₁₀BrF₃N₂O: 383 [M+H].

Intermediate I-1.6.4-(3-Bromo-4-(trifluoromethoxy)benzyl)phthalazin-1(2H)-one was preparedusing 3-bromo-4-trifluoromethoxylbenzaldehyde in step 1. MS (EI) forC₁₆H₁₀BrF₃N₂O₂: 400 [M+H].

Intermediate I-1.7. 4-(3-Bromo-4-methoxybenzyl)phthalazin-1(2H)-one wasprepared using 3-bromo-4-methoxylbenzaldehyde in step 1. MS (EI) forC₁₆H₁₃BrN₂O₂: 356 [M+H].

Intermediate I-1.8. 4-(3-Vromo-4-ethoxybenzyl)phthalazin-1(2H)-one wasprepared using 3-bromo-4-ethoxylbenzaldehyde in step 1. MS (EI) forC₁₇H₁₅BrN₂O₂: 360 [M+H].

Intermediate I-1.9.4-(3-Bromo-4-(2-methoxyethoxy)benzyl)phthalazin-1(2H)-one was preparedusing 3-bromo-4-(2-methoxyethoxy)benzaldehyde in step 1. MS (EI) forC₁₈H₁₇BrN₂O₃: 390 [M+H].

Intermediate I-1.10.4-(3-Bromo-4-(difluoromethoxy)benzyl)phthalazin-1(2H)-one was preparedusing 3-bromo-4-diflouromethoxyethoxybenzaldehyde (R-1.1.) in step 1. MS(EI) for C₁₆H₁₁BrF₂N₂O₂: 382 [M+H].

Intermediate I-1.11. 4-(3-Bromo-5-fluorobenzyl)phthalazin-1(2H)-one wasprepared using 3-bromo-5-flourobenzaldehyde in step 1. MS (EI) forC₁₅H₁₀BrFN₂O: 334 [M+H].

Intermediate I-1.12. 4-(5-bromo-2-fluorobenzyl)phthalazin-1(2H)-one wasprepared using 5-bromo-2-flourobenzaldehyde in step 1. MS (EI) forC₁₅H₁₀BrFN₂O: 334 [M+H].

Intermediate I-1.13. 4-(3-Bromo-2-fluorobenzyl)phthalazin-1(2H)-one wasprepared using 3-bromo-2-flourobenzaldehyde in step 1. MS (EI) forC₁₅H₁₀BrFN₂O: 334 [M+H].

Intermediate I-1.14. 4-(5-Bromo-2,4-difluorobenzyl)phthalazin-(2H)-onewas prepared using 5-bromo-2,4-difluorobenzaldehyde in step 1. MS (EI)for C₁₅H₉BrF₂N₂O: 352 [M+H].

Intermediate I-1.16. 4-(3-Bromo-5-methoxybenzyl)phthalazin-1(2H)-one wasprepared using 3-bromo-5-methoxybenzaldehyde in step 1. MS (EI) forC₁₆H₁₃BrN₂O₂: 346 [M+H].

Intermediate I-1.17. 4-(5-Bromo-2-methoxybenzyl)phthalazin-1 (2H)-onewas prepared using 5-bromo-2-methoxybenzaldehyde in step 1. MS (EI) forC₁₆H₁₃BrN₂O₂: 346 [M+H].

Intermediate I-1.18. 4-(3-bromo-2-methoxybenzyl)phthalazin-1 (2H)-onewas prepared using 3-bromo-2-methoxybenzaldehyde in step 1. MS (EI) forC₁₆H₁₃BrN₂O₂: 346 [M+H].

Intermediate I-1.19. 4-(3-Bromo-4,5-dimethoxybenzyl)phthalazin-1(2H)-onewas prepared using 5-bromo-4,5-dimethoxybenzaldehyde in step 1. MS (EI)for C₁₇H₁₅BrN₂O₃: 376 [M+H].

Intermediate I-1.20. 4-(5-Bromo-2,4-dimethoxybenzyl)phthalazin-1(2H)-onewas prepared using 5-bromo-2,4-dimethoxybenzaldehyde in step 1. MS (EI)for C₁₇H₁₅BrN₂O₃: 376 [M+H].

Intermediate I-1.21.4-(5-Bromo-4-fluoro-2-methoxybenzyl)phthalazin-1(2H)-one was preparedusing 5-bromo-4-fluoro-2-methoxybenzaldehyde (R-2. 1.) in step 1. MS(EI) for C₁₆H₁₂BrFN₂O₂: 364 [M+H].

Intermediate I-1.22.4-(5-Bromo-2-fluoro-4-methoxybenzyl)phthalazin-1(2H)-one was preparedusing 5-bromo-2-fluoro-4-methoxybenzaldehyde (R-2.2.) in step 1. MS (EI)for C₁₆H₁₂BrFN₂O₂: 364 [M+H].

Intermediate I-1.38. 4-((5-Bromofuran-2-yl)methyl)phthalazin-1(2H)-onewas prepared using 5-bromofuran-2-carbaldehyde in step 1. MS (EI) forC₁₃H₉BrN₂O₂: 306 [M+H].

Intermediate I-1.49. 4-(4-Bromo-3-fluorobenzyl)phthalazin-1(2H)-one wasprepared using 4-bromo-3-fluorobenzaldehyde in step 1. MS (EI) forC₁₅H₁₀BrN₂O: 333 [M+H].

Method B

STEP 1. To a suspension of 2-iodobenzoic acid (1b) (2.50 g, 10.00 mol),2-bromo-4-ethynyl-1-fluorobenzene (2b, R-2.1.) (2.20 g, 11.00 mmol) andcesium-carbonate (6.52 g, 20.00 mmol) in dimethyl sulfoxide (10 mL) wasadded cooper(I) iodide (0.19 g, 1.00 mmol) and the reaction mixture wasstirred at room temperature for 18 hours. It was partitioned with ethylacetate (300 mL) and water (50 mL). The organic layer was separated andwashed with water (50 mL), 1M aqueous hydrochloric acid (50 mL) andbrine (2×100 mL), dried over anhydrous sodium sulfate and concentrated.The resulting crude product was purified by gradient silica gel flashchromatography (0-50% ethyl acetate in hexanes) to give(Z)-3-(3-bromo-4-fluorobenzylidene)-isobenzofuran-1(3H)-one (3a) (2.83g, 88%). MS (EI) for C₁₅H₈BrFO₂: 319 [M+H].

STEP 2. To a suspension of(Z)-3-(3-bromo-4-fluorobenzylidene)-isobenzofuran-1(3H)-one (3a) (2.80g, 8.77 mmol) in water (45 mL) was added sodium hydroxide (3.95 mL,39.47 mmol, 10N aqueous solution) and the reaction mixture was heated to90° C. for 1 hour then cooled to 50° C., followed by the addition ofhydrazine hydrate (11.7 mL, 87.70 mmol, 24-25% aqueous solution) andstirred at 90° C. for 18 hours. It was cooled to room temperature andthe pH was adjusted to 4 by the addition of concentrated aqueoushydrochloric acid. The crude mixture was partitioned with ethyl acetate(500 mL) and the organic layer was separated, washed with water (2×100mL) and brine (200 mL), dried over anhydrous sodium sulfate andconcentrated. The precipitated white solid was collected by filtrationto give 4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one (I-1.1.) (2.08 g,71%). MS (EI) for C₁₅H₁₀BrFN₂O: 333 [M+H].

Intermediate I-1.23.4-(3-Bromo-4-fluorobenzyl)-8-fluorophthalazin-1(2H)-one was preparedusing 2-fluoro-6-iodobenzoic acid in step 1. MS (EI) for C₁₅H₉BrF₂N₂O:352 [M+H].

Intermediate I-1.24.4-(3-Bromo-4-fluorobenzyl)-7-fluorophthalazin-1(2H)-one is preparedusing 5-fluoro-2-iodobenzoic acid in step 1. MS (EI) for C₁₅H₉BrF₂N₂O:352 [M+H].

Intermediate I-1.25.4-(3-Bromo-4-fluorobenzyl)-6-fluorophthalazin-1(2H)-one was preparedusing 4-fluoro-2-iodobenzoic acid in step 1. 1H NMR (300 MHz, d₆-DMSO):12.57 (s, 1H), 8.24 (d, 1H), 7.96 (m, 1H), 7.78 (m, 1H), 7.56 (m, 1H),7.26 (m, 1H), 7.18 (m, 1H), 4.35 (s, 2H). MS (EI) for C₁₅H₉BrF₂N₂O: 352[M+H].

Intermediate I-1.26.4-(3-Bromo-4-fluorobenzyl)-5-fluorophthalazin-1(2H)-one was preparedusing 3-fluoro-2-iodobenzoic acid in step 1. MS (EI) for C₁₅H₉BrF₂N₂O:352 [M+H].

Intermediate I-1.28.4-(3-Bromo-4-fluorobenzyl)-6,7-difluorophthalazin-1(2H)-one is preparedusing 4,5-difluoro-2-iodobenzoic acid in step 1. MS (EI) forC₁₅H₈BrF₃N₂O: 370 [M+H].

Intermediate I-1.36.4-(3-Bromo-4-fluorobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one wasprepared using 2-bromo-4,5-dimethoxybenzoic acid in step 1. 1H NMR (300MHz, d₆-DMSO): 12.56 (s, 1H), 7.58 (s. 1H), 7.55 (m, 1H), 7.42, (s, 1H),7.23 (m, 2H), 4.28 (s, 2H) 3.94 (s, 3H), 3.93 (s, 3H). MS (EI) forC₁₇H₁₄BrFN₂O₃: 394 [M+H}.

Method C

STEP 1. To a solution of N-(quinolin-8-yl)benzamide (1c, R-3.1.) (1.24g, 5.00 mmol) 2-bromo-4-ethynyl-1-fluorobenzene (2b) (R-2.1.) (2.00 g,10.00 mmol) and potassium-carbonate (1.40 g, 10.00 mmol) inN,N-dimethylformamide (20 mL) was added cooper(II) acetate (0.91 g, 5.00mmol) and the reaction mixture was stirred at 80° C. for 18 hours underoxygen atmosphere. The reaction mixture was cooed to room temperature,diluted with dichloromethane (250 mL) and filtered through a pad ofCelite. The organic layer was washed with water (2×50 mL) and brine(2×100 mL), dried over anhydrous sodium sulfate and concentrated. Theresulting crude product was purified by gradient silica gel flashchromatography (0-5% methanol in dichloromethane) to give(Z)-3-(3-bromo-4-fluorobenzylidene)-2-(quinolin-8-yl)isoindolin-1-one(3b) (1.74 g, 78%). MS (EI) for C₂₄H₁₄BrFN₂O: 446 [M+H].

STEP 2. To a suspension of3-(3-bromo-4-fluorobenzylidene)-2-(quinolin-8-yl)isoindolin-1-one (3b)(1.74 g, 3.90 mmol) in a mixture of water (25 mL) and ethanol (15 mL)10N aqueous sodium hydroxide (3.90 mL, 39.0 mmol) was added and thereaction mixture was heated to reflux for 1 hour. Upon cooling it toroom temperature hydrazine monohydrate (64-65 wt %, 3.0 mL, 39.0 mmol)was added to the reaction mixture and it was stirred at 90° C.overnight. Upon cooling in ice water, the pH was adjusted to 4-5 by theaddition of concentrated aqueous hydrochloric acid and it waspartitioned with ethyl acetate (250 mL). The organic layer was separatedand washed with water (2×100 mL) and brine (100 mL), dried overanhydrous sodium sulfate and concentrated. Upon removing the solvent theproduct has precipitated; it was collected by filtration washed withhexanes and dried in vacuo to give 4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one (I-1.1) (1.2 g, 94%). MS (EI) for C₁₅H₁₀BrFN₂O: 333[M+H].

Intermediate I-1.27.4-(3-Bromo-4-fluorobenzyl)-5,8-difluorophthalazin-1(2H)-one was preparedusing 2,5-difluoro-N-(quinolin-8-yl)benzamide (R-3.2.) in step 1. MS(EI) for C₁₅H₈BrF₃N₂O: 370 [M+H].

Intermediate I-1.29.4-(3-Bromo-4-fluorobenzyl)-8-methylphthalazin-1(2H)-one is preparedusing 2-methyl-N-(quinolin-8-yl)benzamide (R-3.3.) in step 1. MS (EI)for C₁₆H₁₂BrFN₂O: 348 [M+H].

Intermediate I-1.30.4-(3-Bromo-4-fluorobenzyl)-7-methylphthalazin-1(2H)-one was preparedusing 3-methyl-N-(quinolin-8-yl)benzamide (R-3.4.) in step 1. 1H NMR(300 MHz, d₆-DMSO): 12.52 (s, 1H), 8.16 (s, 1H), 7.78 (d, 1H), 7.64 (d,1H), 7.57 (m, 1H), 7.22 (m, 2H), 4.28 (s, 2H), 2.43 (s, 3H). MS (EI) forC₁₆H₁₂BrFN₂O: 348 [M+H].

Intermediate I-1.31.4-(3-bromo-4-fluorobenzyl)-6-methylphthalazin-1(2H)-one was preparedusing 4-methyl-N-(quinolin-8-yl)benzamide (R-3.5.) in step 1. 1H NMR(300 MHz, d₆-DMSO): 12.51 (s, 1H), 8.14 (d, 1H), 7.76 (s, 1H), 7.62 (d,1H), 7.57 (m, 1H), 7.22 (m, 2H), 4.28 (s, 2H), 2.45 (s, 3H). MS (EI) forC₁₆H₁₂BrFN₂O: 348 [M+H].

Intermediate I-1.32.4-(3-Bromo-4-fluorobenzyl)-6-chlorophthalazin-1(2H)-one is preparedusing 4-methyl-N-(quinolin-8-yl)benzamide (R-3.6.) in step 1. MS (EI)for C₁₅H₉BrClFN₂O: 368 [M+H].

Intermediate I-1.33.4-(3-Bromo-4-fluorobenzyl)-6-(trifluoromethyl)phthalazin-1(2H)-one isprepared using N-(quinolin-8-yl)-4-(trifluoromethyl)benzamide (R-3.7.)in step 1. MS (EI) for C₁₆H₉BrF₄N₂₀: [M+H]402.

Intermediate I-1.34.4-(3-Bromo-4-fluorobenzyl)-6-methoxyphthalazin-1(2H)-one is preparedusing 4-methoxy-N-(quinolin-8-yl)benzamide (R-3.8.) in step 1. MS (EI)for C₁₆H₁₂BrFN₂O₂: [M+H] 364.

Intermediate I-1.35. 4-(3-Bromo-4-fluorobenzyl)-6-(trifluoromethoxy)phthalazin-1(2H)-one is prepared usingN-(quinolin-8-yl)-4-(trifluoromethoxy) benzamide (R-3.9.) in step 1. MS(EI) for C₁₆H₉BrF₄N₂O₂: [M+H] 418.

Intermediate I-1.37.4-(3-Bromo-4-fluorobenzyl)-5,7-dimethoxyphthalazin-1(2H)-one is preparedusing 3,5-dimethoxy-N-(quinolin-8-yl)benzamide (R-3.10.) in step 1. MS(EI) for C₁₇H₁₄BrFN₂O₃: 394.

Intermediate 24-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)phthalazin-1(2H)-one(I-2.1.)

A solution of 4-(3-bromo-4-fluorobenzyl) phthalazin-1(2H)-one (I-1.1.)(0.33 g, 1.00 mmol), bis (pinacolato)diboron (0.28 g, 1.10 mmol),potassium acetate (0.30 g, 3.00 mmol) anddichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (37 mg, 0.05 mmol) in dimethyl sulfoxide (3.0 mL)was heated to 80° C. for three hours. Upon cooling the reaction mixtureto room temperature, it was diluted with ethyl acetate (100 mL) andfiltered through a pad of Celite. The filtrate was partitioned with 1Maqueous hydrochloric acid (50 ml). The organic layer was separated andwashed with brine (2×50 mL), dried over anhydrous sodium sulfate andconcentrated. The resulting crude was purified by gradient silica gelflash chromatography (0-50% ethyl acetate in hexanes) to give4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)phthalazin-1(2H)-one (I-2.1.) (0.33 g, 87%). (TLC 30% ethyl acetate in hexanes). MS(EI) for C₂₁H₂₂BFN₂O₃: 381 [M+H].

Intermediate 34-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-3.1.)

Method A.

A solution of 4-(3-bromo-4-fluorobenzyl) phthalazin-1 (2H)-one (I-1.1.)(0.33 g, 1.00 mmol),2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.26 g,1.00 mmol) and potassium carbonate (0.41 g, 3.00 mmol) in a mixture of1,4-dioxane (4.5 mL) and water (0.5 mL) was degassed by repeatedlyevacuating the reaction wessel then bubbling nitrogen gas through thesolution, followed by the addition ofdichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium (II)dichloromethane adduct (41 mg, 0.05 mmol) and stirring the reactionmixture at 98° C. for 18 hours. It was cooled to room temperature andpartitioned with ethyl acetate (100 mL) and 1M aqueous hydrochloric acid(50 ml). The organic layer was washed with 1M aqueous hydrochloric acid(2×50 ml) and brine (2×50 mL), dried over anhydrous sodium sulfate andconcentrated. The resulting crude was purified by gradient silica gelflash chromatography (5-75% ethyl acetate in hexanes) to give4-((3′-amino-6-fluoro-4′-nitro-[1,1′-biphenyl]-3-yl)methyl) phthalazin-1(2H)-one (I-3.1.) (0.26 g, 67%). (TLC 50% ethyl acetate in hexanes). 1HNMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.26 (d, 1H), 8.12 (s, 1H), 8.02(d, 1H), 7.92 (t, 1H), 7.86 (t, 1H), 7.60 (m, 4H), 7.26 (m, 2H), 7.10(d, 1H), 4.35 (s, 2H). MS (EI) for C₂₁H₁₅FN₄O₃: 391 [M+H].

Intermediate I-3.2.4-((4′-Amino-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(3-bromobenzyl)phthalazin-1(2H)-one (I-1.2.). MS(EI) for C₂₁H₁₆N₄O₃: 373 [M+H].

Intermediate I-3.3.4-((4′-Amino-6-chloro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(3-bromo-4-chlorobenzyl)phthalazin-1(2H)-one(I-1.3.). MS (EI) for C₂₁H₁₅ClN₄O₃: 407 [M+H].

Intermediate I-3.4.4-((4′-Amino-6-methyl-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(3-bromo-4-methylbenzyl)phthalazin-1(2H)-one(I-1.4.). MS (EI) for C₂₂H₁₈N₄O₃: 387 [M+H].

Intermediate I-3.5.4-((3′-Amino-4′-nitro-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-(3-bromo-4-(trifluoromethyl)benzyl)phthalazin-1(2H)-one (I-1.5.). MS(EI) for C₂₂H₁₅F₃N₄O₃: 441 [M+H].

Intermediate I-3.6.4-((4′-Amino-3′-nitro-6-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one was prepared using4-(3-bromo-4-(trifluoromethoxy)benzyl)phthalazin-1(2H)-one (I-1.6.). MS(EI) for C₂₂H₁₅F₃N₄O₄: 457 [M+H].

Intermediate I-3.7.4-((4′-Amino-6-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one was prepared using4-(3-bromo-4-methoxybenzyl)phthalazin-1(2H)-one (I-1.7.). 1H NMR (300MHz, d₆-DMSO): 12.55 (s, 1H), 8.26 (d, 1H), 8.04 (s, 1H), 8.02 (d, 1H),7.88 (t, 1H), 7.85 (t, 1H), 7.56 (d, 1H), 7.46 (m, 2H), 7.32 (s, 1H),7.20 (d, 1H), 7.05 (m, 2H), 4.28 (s, 2H), 3.72 (s, 3H). MS (EI) forC₂₂H₁₈N₄O₄: 403.

Intermediate I-3.8.4-((4′-Amino-6-ethoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(3-bromo-4-ethoxybenzyl)phthalazin-1(2H)-one(I-1.8.). MS (EI) for C₂₃H₂₀N₄O₄: 417 [M+H].

Intermediate I-3.9.4-((4′-Amino-6-(2-methoxyethoxy)-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1 (2H)-one was prepared using4-(3-bromo-4-(2-methoxyethoxy)benzyl)phthalazin-1(2H)-one (I-1.9.). MS(EI) for C₂₄H₂₂N₄O₅: 47 [M+H].

Intermediate I-3.10.4-((4′-Amino-6-(difluoromethoxy)-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one was prepared using4-(3-bromo-4-(difluoromethoxy)benzyl)phthalazin-1(2H)-one (I-1.10.). MS(EI) for C₂₂H₁₆F₂N₄O₄: 439 [M+H].

Intermediate I-3.11.4-((4′-Amino-5-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(3-bromo-5-fluorobenzyl)phthalazin-1(2H)-one(I-1.11.). MS (EI) for C₂₁H₁₅FN₄O₃: 391 [M+H].

Intermediate I-3.12.4-((4′-Amino-4-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(5-bromo-2-fluorobenzyl)phthalazin-1(2H)-one(I-1.12.). MS (EI) for C₂₁H₁₅FN₄O₃: 391 [M+H].

Intermediate I-3.13.4-((4′-Amino-2-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(3-bromo-2-fluorobenzyl)phthalazin-1(2H)-one(I-1.13.). MS (EI) for C₂₁H₁₅FN₄O₃: 391 [M+H].

Intermediate I-3.14.4-((4′-Amino-4,6-difluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(5-bromo-2,4-difluorobenzyl)phthalazin-1(2H)-one(I-1.14.). MS (EI) for C₂₁H₁₄F₂N₄O₃: 409 [M+H].

Intermediate I-3.16.4-((4′-Amino-5-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(3-bromo-5-methoxybenzyl)phthalazin-1(2H)-one(I-1.16.). MS (EI) for C₂₂H₁₈N₄O₄:403 [M+H].

Intermediate I-3.17.4-((4′-Amino-4-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(5-bromo-2-methoxybenzyl)phthalazin-1(2H)-one(I-1.17.). MS (EI) for C₂₂H₁₈N₄O₄:403 [M+H].

Intermediate I-3.18.4-((4′-Amino-2-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(3-bromo-2-methoxybenzyl)phthalazin-1(2H)-one(I-1.18.). MS (EI) for C₂2H₁₈N₄O₄:403 [M+H].

Intermediate I-3.19.4-((4′-Amino-5,6-dimethoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(3-bromo-4,5-dimethoxybenzyl)phthalazin-1(2H)-one(I-1.19.). MS (EI) for C₂₃H₂₀N₄O₅: 433 [M+H].

Intermediate I-3.20.4-((4′-Amino-4,6-dimethoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(5-bromo-2,4-dimethoxybenzyl)phthalazin-1(2H)-one(I-1.20.). MS (EI) for C₂₃H₂₀N₄O₅: 433 [M+H].

Intermediate I-3.21.4-((4′-Amino-6-fluoro-4-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one was prepared using4-(5-bromo-4-fluoro-2-methoxybenzyl)phthalazin-1(2H)-one (I-1.21.). MS(EI) for C₂₂H₁₇FN₄O₄: 421 [M+H].

Intermediate I-3.22.4-((4′-Amino-4-fluoro-6-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one was prepared using4-(5-bromo-2-fluoro-4-methoxybenzyl)phthalazin-1(2H)-one (I-1.22.). MS(EI) for C₂₂H₁₇FN₄O₄: 421 [M+H].

Intermediate I-3.23.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-8-fluorophthalazin-1(2H)-one was be prepared using4-(3-bromo-4-fluorobenzyl)-8-fluorophthalazin-1(2H)-one (I-1.23.). MS(EI) for C₂₁H₁₄F₂N₄O₃: 409 [M+H].

Intermediate I-3.24.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-7-fluorophthalazin-1(2H)-one is prepared using4-(3-bromo-4-fluorobenzyl)-7-fluorophthalazin-1(21H)-one (I-1.24.). MS(EI) for C₂₁H₁₄F₂N₄O₃: 409 [M+H].

Intermediate I-3.25.4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-fluorophthalazin-1(2H)-one was prepared using4-(3-bromo-4-fluorobenzyl)-6-fluorophthalazin-1(2H)-one (I-1.25.). MS(EI) for C₂₁H₁₄F₂N₄O₃: 409 [M+H].

Intermediate I-3.26.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-5-fluorophthalazin-1(2H)-one was prepared using4-(3-bromo-4-fluorobenzyl)-5-fluorophthalazin-1(2H)-one (I-1.26.). MS(EI) for C₂₁H₁₄F₂N₄O₃: 409 [M+H].

Intermediate I-3.27.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-5,8-difluoro-phthalazin-1(2H)-one was prepared using4-(3-bromo-4-fluorobenzyl)-5,8-difluorophthalazin-1(2H)-one (I-1.27.).MS (EI) for C₂₁H₁₃F₃N₄O₃: 427 [M+H].

Intermediate I-3.28.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6,7-difluoro-phthalazin-1(2H)-one is prepared using4-(3-bromo-4-fluorobenzyl)-6,7-difluorophthalazin-1(2H)-one (I-1.28.).MS (EI) for C₂₁H₁₃F₃N₄O₃: 427 [M+H].

Intermediate I-3.29.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-8-methylphthalazin-1(2H)-onewas prepared using4-(3-bromo-4-fluorobenzyl)-8-methylphthalazin-1(2H)-one (I-1.29.). MS(EI) for C₂₂H₁₇FN₄O₃: 405 [M+H].

Intermediate I-3.30.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-7-methylphthalazin-1(2H)-onewas prepared using4-(3-bromo-4-fluorobenzyl)-7-methyl-phthalazin-1(2H)-one (I-1.30.). MS(EI) for C₂₂H₁₇FN₄O₃: 405 [M+H].

Intermediate I-3.31.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-methylphthalazin-1(2H)-onewas prepared using4-(3-bromo-4-fluorobenzyl)-6-methylphthalazin-1(2H)-one (I-1.31.). MS(EI) for C₂₂H₁₇FN₄O₃: 405 [M+H].

Intermediate I-3.32.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-chlorophthalazin-1(2H)-oneis prepared using4-(3-bromo-4-fluorobenzyl)-6-chlorophthalazin-1(2H)-one (I-1.32.). MS(EI) for C₂₁H₁₄ClFN₄O₃: 425 [M+H}.

Intermediate I-3.33.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoro-methyl)phthalazin-1(2H)-oneis prepared using 4-(3-bromo-4-fluorobenzyl)-6-(trifluoromethyl)phthalazin-1(2H)-one (I-1.33.). MS (EI) for C₂₂H₁₄F₄N₄O₃: 459 [M+H].

Intermediate I-3.34.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-methoxy-phthalazin-1(2H)-one is prepared using4-(3-bromo-4-fluorobenzyl)-6-methoxyphthalazin-1(2H)-one (I-1.33.). MS(EI) for C₂₂H₁₇FN₄O₄: 421 [M+H].

Intermediate I-3.35.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoro-methoxy)phthalazin-1(2H)-oneis prepared using4-(3-bromo-4-fluorobenzyl)-6-(trifluoro-methoxy)phthalazin-1(2H)-one(I-1.35.). MS (EI) for C₂₂H₁₄F₄N₄O₄: 475 [M+H].

Intermediate I-3.36.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6,7-dimethoxy-phthalazin-1(2H)-oneone was prepared using4-(3-bromo-4-fluorobenzyl)-6,7-dimethoxyphthalazin-1(2H)-one (I-1.36.).MS (EI) for C₂₃H₁₉FN₄O₅: 451 [M+H].

Intermediate I-3.37.4-((4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-5,7-dimethoxy-phthalazin-1(2H)-oneis prepared using4-(3-bromo-4-fluorobenzyl)-5,7-dimethoxyphthalazin-1(2H)-one (I-1.37.).MS (EI) for C₂₃H₁₉FN₄O₅: 451 [M+H].

Intermediate I-3.38.4-((5-(4-Amino-3-nitrophenyl)furan-2-yl)methyl)phthalazin-1(2H)-one wasprepared using 4-((5-bromofuran-2-yl)methyl)phthalazin-1(2H)-one(I-1.38.). MS (EI) for C₁₉H₁₄N₄O₄: 363 [M+H].

Intermediate I-3.49.4-((4′-Amino-2-fluoro-3′-nitro-[1,1′-biphenyl]-4-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-(4-bromo-3-fluorobenzyl)phthalazin-1(2H)-one(I-1.49.). MS (EI) for C₂₁H₁₅FN₄O₃: 391 [M+H].

Method B

A solution of4-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)phthalazin-1(2H)-one(I-2.1.) (0.38 g, 1.00 mmol), 4-bromo-2-nitroaniline (0.22 g, 100 mmol)and potassium carbonate (0.41 g, 3.00 mmol) in a mixture of 1,4-dioxane(4.5 mL) and water (0.5 mL) was purged with nitrogen gas for 20 minutes,followed by the addition of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (41 mg, 0.05 mmol) andthe reaction mixture was stirred at 98° C. for 18 hours. Upon cooling itto room temperature it was diluted with ethyl acetate (50 mL) and themixture was filtered through a pad of Celite, then washed with anadditional portion of ethyl acetate (50 mL). The combined phases werewashed with 1M aqueous hydrochloric acid (2×50 ml) and brine (2×50 mL),dried over anhydrous sodium sulfate and concentrated. The resultingcrude was purified by gradient silica gel flash chromatography (5-75%ethyl acetate in hexanes) to give4-((3′-amino-6-fluoro-4′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.1.) (0.28 g, 73%). 1H NMR (300 MHz, d₆-DMSO):12.56 (s, 1H), 8.26 (d, 1H), 8.12 (s, 1H), 8.02 (d, 1H), 7.92 (t, 1H),7.86 (t, 1H), 7.60 (m, 4H), 7.26 (m, 2H), 7.10 (d, 1H), 4.35 (s, 2H). MS(EI) for C₂₁H₁₅FN₄O₃: 391 [M+H].

Intermediate I-3.40.4-((4′-Amino-3′,6-difluoro-5′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one was prepared using 4-bromo-2-fluoro-6-nitroaniline MS (EI) forC₂₁H₁₄F₂N₄O₃: 409 [M+H].

Intermediate I-3.41.4-((4′-Amino-2′,6-difluoro-5′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one was prepared using 4-bromo-3-fluoro-2-nitroaniline MS (EI) forC₂₁H₁₄F₂N₄O₃: 409 [M+H].

Intermediate I-3.42.4-((4′-Amino-2′,6-difluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using 4-bromo-5-fluoro-2-nitroaniline MS (EI) forC₂₁H₁₄F₂N₄O₃: 409 [M+H].

Intermediate I-3.44.4-(3-(6-Amino-5-nitropyridin-2-yl)-4-fluorobenzyl)phthalazin-1 (2H)-onewas prepared using 6-bromo-3-nitropyridin-2-amine MS (EI) forC₂₀H₁₄FN₅O₃: 392 [M+H].

Intermediate I-3.45.4-(3-(6-Amino-5-nitropyridin-3-yl)-4-fluorobenzyl)phthalazin-1 (2H)-oneis prepared using 5-bromo-3-nitropyridin-2-amine MS (EI) forC₂₀H₁₄FN₅O₃: 392 [M+H].

Intermediate I-3.46.4-(3-(4-Amino-5-nitropyridin-2-yl)-4-fluorobenzyl)phthalazin-1 (2H)-oneis prepared using 2-bromo-5-nitropyridin-4-amine MS (EI) forC₂₀H₁₄FN₅O₃: 392 [M+H].

Intermediate I-3.47.4-(3-(6-Amino-2-methyl-5-nitropyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one was prepared using 5-bromo-6-methyl-3-nitropyridin-2-amine MS(EI) for C₂₁H₁₆FN₅O₃: 406 [M+H].

Intermediate I-3.48.4-(3-(6-Amino-4-methyl-5-nitropyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one is prepared using 5-bromo-4-methyl-3-nitropyridin-2-amine MS(EI) for C₂₁H₁₆FN₅O₃: 406 [M+H].

Method C

STEP 1. To a solution of4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-carbaldehyde (4, R-4.1.)(2.08 g, 8.0 mmol) ad dimethyl3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (1a) (3.70 g, 16.0 mmol)in tetrahydrofuran (50 mL) trimethylamine (11.2 mL, 80.0 mmol) was addeddropwise and the reaction mixture was heated to reflux for 18 hoursunder nitrogen atmosphere. Upon cooling it to room temperature, thesolvent was concentrated and the residue was partitioned with ethylacetate (300 mL) and 2M aqueous hydrochloric acid (100 mL). The organiclayer was separated, washed with 2M aqueous hydrochloric acid (2×100mL), brine (150 mL), 1M aqueous sodium hydroxide (2×100 mL), brine (150mL), 1M aqueous hydrochloric acid (100 mL) and bine (150 mL), dried overanhydrous sodium sulfate and the solvent was concentrated. The resultingcrude solid was triturated with ethyl acetate and the solid wascollected by filtration to give(E/Z)-3-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methylene)isobenzofuran-1(3H)-one(5) (2.65 g, 88%) as a brown solid. A portion of the crude product wasrecrystallized from ethyl acetate to give(Z)-3-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methylene)isobenzofuran-1(3H)-one.1H NMR (300 MHz, d₆-DMSO): 8.18 (s, 1H), 8.10 (d, 1H), 7.95 (d, 1H),7.88 (m, 3H), 7.70 (s, 3H), 7.67 (t, 1H), 7.42 (dd, 1H), 7.21 (d, 1H),7.07 (s, 1H). MS (EI) for C₂₁H₁₃FN₂O₄: 377 [M+H].

STEP 2. To a suspension of(E/Z)-3-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methylene)isobenzofuran-1(3H)-one (5) (1.14 g, 3.00 mmol) in N,N-dimethylformamide(10 mL) N-methylmorpholine (0.70 mL, 6.00 mmol) was added, followed bythe addition of a 1M solution of hydrazine in tetrahydrofuran (3.75 mL,3.75 mmol). The reaction mixture was heated to 75° C. for 18 hours. Itwas cooled to room temperature and partitioned with ethyl acetate (250mL) and 2M aqueous hydrochloric acid (100 mL). The organic layer wasseparated and washed with 2M aqueous hydrochloric acid⁴ (100 mL) andbrine (2×150 mL), dried over anhydrous sodium sulfate and the solventwas concentrated. The resulting crude was triturated with ethanol andthe yellow solid was collected by filtration washed with 10% ethylacetate in hexanes and air dried to give4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.1.) (1.05 g, 89%). MS (EI) for C₂₁H₁₅FN₄O₃:391 [M+H].

Intermediate I-3.15.4-((4′-Amino-5,6-difluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-carbaldehyde (R-4.2.) instep 1. MS (EI) for C₂₁H₁₄F₂N₄O₃: 408 [M+H].

Intermediate I-3.39.4-((4-(4-Amino-3-nitrophenyl)furan-2-yl)methyl)phthalazin-1(2H)-one wasprepared using 4-(4-amino-3-nitrophenyl)furan-2-carbaldehyde (R-4.3.) instep 1. MS (EI) for C₁₉H₁₄N₄O₄: 363 [M+H].

Intermediate 44-((3′,4′-diamino-5′-chloro-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-4.1.)

STEP 1 To a solution of4-((3′-amino-6-fluoro-4′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-2.1.) (0.54 g, 1.38 mmol) inN,N-dimethylformamid (10 mL) was added N-chlorosuccinimide (0.18 g, 1.38mmol) in one portion. The reaction mixture was stirred at roomtemperature for 18 hours. The mixture was partitioned with ethyl acetate(100 mL) and 1M aqueous hydrochloric acid (50 ml). The organic layer wasseparated and washed with 1M aqueous hydrochloric acid (50 ml) and brine(2×50 mL), dried over anhydrous sodium sulfate and concentrated. Theresulting crude was purified by gradient silica gel flash chromatography(5-50% ethyl acetate in hexanes) to give4-((4′-amino-3′-chloro-6-fluoro-5′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (6) (0.55 g, 93%). 1H NMR (300 MHz, d₆-DMSO): 12.57 (s, 1H),8.27 (d, 1H), 8.12 (s, 1H), 8.02 (d, 1H), 7.90-7.86 (m, 2H), 7.58 (m,4H), 7.26 (s, 1H), 7.10 (d, 1H), 4.34 (s, 2H). MS (EI) forC₂₁H₁₄ClFN₄O₃: 426 [M+H].

STEP 2. A suspension of4-((4′-amino-3′-chloro-6-fluoro-5′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (6) (0.33 g, 0.78 mmol), ammonium formate (0.98 g,15.54 mmol) and iron metal powder (0.43 g, 7.70 mmol) in a mixture oftetrahydrofuran (25 mL) and water (5 mL) was heated to 70° C. for 18hours. It was cooled to room temperature and the solid was removed byfiltering the reaction mixture through a pad of Celite. The residue waspartitioned with ethyl acetate (250 mL) and saturated aqueous sodiumbicarbonate (100 ml). The organic layer was separated, washed withsaturated aqueous sodium bicarbonate (50 ml), brine (2×100 mL), driedover anhydrous sodium sulfate and concentrated. The resulting crude waspurified by gradient silica gel flash chromatography (10-80% ethylacetate in hexanes) to give4-((4′,5′-diamino-2′-chloro-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-4.1.) (0.17 g, 56%). The crude product was used without furtherpurification. MS (EI) for C₂₁H₁₆ClFN₄O: 395 [M+H].

Intermediate 54-((3′4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.1.)

To a suspension of4-((3′-amino-6-fluoro-4′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.1.) (0.25 g, 0.64 mmol) and ammonium formate(0.81 g, 12.80 mmol) in methanol (25 mL) palladium on activated carbon(0.1 g, 10 wt % loading on wet support, Degussa type) was added and thereaction mixture was stirred at 62° C. for 18 hours. It was cooled toroom temperature and the catalyst was removed filtering the reactionmixture through a pad of Celite; the solvent was concentrated, theresidue was partitioned with ethyl acetate (100 mL) and saturatedaqueous sodium bicarbonate (50 ml). The organic layer was separated,washed with saturated aqueous sodium bicarbonate (2×25 ml) and brine(2×100 mL), dried over anhydrous sodium sulfate and concentrated to give4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.1.) as light brown solid (0.22 g, 96%). The crude product was usedwithout further purification. MS (EI) for C₂₁H₁₇FN₄O: 361 [M+H].

Intermediate I-5.2.4-((3′,4′-Diamino-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one wasprepared using4-((4′-amino-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.2.). MS (EI) for C₂₁H₁₈N₄O: 343 [M+H].

Intermediate I-5.3.4-((3′,4′-Diamino-6-chloro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-6-chloro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.3.). MS (EI) for C₂₁H₁₇ClN₄O: 377 [M+H].

Intermediate I-5.4.4-((3′,4′-Diamino-6-methyl-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-6-methyl-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.4.). MS (EI) for C₂₂H₂₀N₄O: 357 [M+H].

Intermediate I-5.5.4-((3′,4′-Diamino-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((3′-amino-4′-nitro-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.5.). MS (EI) for C₂₂H₁₇F₃N₄O: 410 [M+H].

Intermediate I-5.6.4-((3′,4′-Diamino-6-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one was prepared using4-((4′-amino-3′-nitro-6-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.6.). MS (EI) for C₂₂H₁₇F₃N₄O₂: 427 [M+H].

Intermediate I-5.7.4-((3′,4′-Diamino-6-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-6-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.7.). MS (EI) for C₂₂H₂₀N₄O₂: 372 [M+H].

Intermediate I-5.8.4-((3′,4′-Diamino-6-ethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-6-ethoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.8.). MS (EI) for C₂₃H₂₂N₄O₂: 387 [M+H].

Intermediate I-5.9.4-((3′,4′-Diamino-6-(2-methoxyethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one was prepared using4-((4′-amino-6-(2-methoxyethoxy)-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1 (2H)-one (1-3.9.). MS (EI) for C₂₄H₂₄N₄O₃: 417 [M+H].

Intermediate I-5.10.4-((3′,4′-Diamino-6-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-6-(difluoromethoxy)-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1 (2H)-one (I-3.10.). MS (EI) for C₂₂H₁₈F₂N₄O₂: 409 [M+H].

Intermediate I-5.11.4-((3′,4′-Diamino-5-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-5-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.11.). MS (EI) for C₂₁H₁₇FN₄O: 361 [M+H].

Intermediate I-5.12.4-((3′,4′-Diamino-4-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-4-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.12.). MS (EI) for C₂₁H₁₇FN₄O: 361 [M+H].

Intermediate I-5.13.4-((3′,4′-Diamino-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-2-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.13.). MS (EI) for C₂₁H₁₇FN₄O: 361 [M+H].

Intermediate I-5.14.4-((3′,4′-Diamino-4,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-4,6-difluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.14.). MS (EI) for C₂₁H₁₆F₂N₄O: 379 [M+H].

Intermediate I-5.15.4-((3′,4′-Diamino-5,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one was prepared using4-((4′-amino-5,6-difluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.15.). MS (EI) for C₂₁H₁₆F₂N₄O: 379 [M+H].

Intermediate I-5.16.4-((3′,4′-Diamino-5-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-5-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.16.). MS (EI) for C₂₂H₂₀N₄O₂: 373 [M+H].

Intermediate I-5.17.4-((3′,4′-Diamino-4-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-4-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.17.). MS (EI) for C₂₂H₂₀N₄O₂: 373 [M+H].

Intermediate I-5.18.4-((3′,4′-Diamino-2-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-2-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.18.). MS (EI) for C₂₂H₂₀N₄O₂: 373 [M+H].

Intermediate I-5.19.4-((3′,4′-Diamino-5,6-dimethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-5,6-dimethoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.19.). MS (EI) for C₂₃H₂₂N₄O₃: 403 [M+H].

Intermediate I-5.20.4-((3′,4′-Diamino-4,6-dimethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-4,6-dimethoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.20.). MS (EI) for C₂₃H₂₂N₄O₃: 403 [M+H].

Intermediate I-5.21.4-((3′,4′-Diamino-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-6-fluoro-4-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.21.). MS (EI) for C₂₂H₁₉FN₄O₂: 391 [M+H].

Intermediate I-5.22.4-((3′,4′-Diamino-4-fluoro-6-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-4-fluoro-6-methoxy-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-3.22.). MS (EI) for C₂₂H₁₉FN₄O₂: 391 [M+H].

Intermediate I-5.23.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-8-fluorophthalazin-1(2H)-onewas prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-8-fluorophthalazin-1(2H)-one(1-3.23.). MS (EI) for C₂₁H₁₆F₂N₄O: 379 [M+H].

Intermediate I-5.24.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-7-fluorophthalazin-1(2H)-oneis prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-7-fluorophthalazin-1(2H)-one(1-3.24.). MS (EI) for C₂₁H₁₆F₂N₄O: 379 [M+H].

Intermediate I-5.25.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-fluorophthalazin-1(2H)-onewas prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-fluorophthalazin-1(2H)-one(1-3.25.). MS (EI) for C₂₁H₁₆F₂N₄O: 379 [M+H].

Intermediate I-5.26.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5-fluorophthalazin-1(2H)-one was prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-5-fluorophthalazin-1(2H)-one (1-3.26.). MS (EI) for C₂₁H₁₆F₂N₄O: 379 [M+H].

Intermediate I-5.27.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5,8-difluorophthalazin-1(2H)-onewas prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-5,8-difluorophthalazin-1(2H)-one(1-3.27.). MS (EI) for C₂₁H₁₅F₃N₄O: 397 [M+H].

Intermediate I-5.28.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6,7-difluorophthalazin-1(2H)-oneis prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6,7-difluorophthalazin-1(2H)-one(1-3.28.). MS (EI) for C₂₁H₁₅F₃N₄O: 397 [M+H].

Intermediate I-5.29.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-8-methylphthalazin-1(2H)-onewas prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-8-methylphthalazin-1(2H)-one(1-3.29.). MS (EI) for C₂₂H₁₉FN₄O: 375 [M+H].

Intermediate I-5.30.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-7-methylphthalazin-1(2H)-onewas prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-7-methylphthalazin-1(2H)-one(1-3.30.). MS (EI) for C₂₂H₁₉FN₄O: 375 [M+H].

Intermediate I-5.31.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-methylphthalazin-1(2H)-onewas prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-methylphthalazin-1(2H)-one(1-3.31.). MS (EI) for C₂₂H₁₉FN₄O: 375 [M+H].

Intermediate I-5.32.6-Chloro-4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onecan is using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-chloro-phthalazin-1(2H)-one(1-3.32.). MS (EI) for C₂₁H₁₆ClFN₄O: 395 [M+H].

Intermediate I-5.33.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoromethyl)phthalazin-1(2H)-one was prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoromethyl)phthalazin-1(2H)-one(I-3.33.). MS (EI) for C₂₂H₁₆F₄N₄O: 429 [M+H].

Intermediate I-5.34.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-methoxy-phthalazin-1(2H)-oneis prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-methoxyphthalazin-1(2H)-one(1-3.34.). MS (EI) for C₂₂H₁₉FN₄O₂: 391 [M+H].

Intermediate I-5.35.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoromethoxy)phthalazin-1(2H)-one was prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoromethoxy)phthalazin-1(2H)-one(I-3.35.). MS (EI) for C₂₂H₁₆F₄N₄O₂: 445 [M+H].

Intermediate I-5.36.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6,7-dimethoxyphthalazin-1(2H)-onewas prepared using4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-6,7-dimethoxyphthalazin-1(2H)-one (1-3.36.). MS (EI) for C₂₃H₂₁FN₄O₃: 421.

Intermediate I-5.37.4-((3′,4′-Diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5,7-dimethoxy-phthalazin-1(2H)-oneis prepared using 4-((4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)-5,7-dimethoxyphthalazin-1(2H)-one (1-3.37.). MS (EI) forC₂₃H₂₁FN₄O₃: 421.

Intermediate I-5.38.4-((5-(3,4-Diaminophenyl)furan-2-yl)methyl)phthalazin-1(2H)-one wasprepared using4-((5-(4-amino-3-nitrophenyl)furan-2-yl)methyl)phthalazin-1(2H)-one(I-3.38.). MS (EI) for C₁₉H₁₆N₄O₂: 333 [M+H].

Intermediate I-5.39.4-((4-(3,4-Diaminophenyl)furan-2-yl)methyl)phthalazin-1 (2H)-one wasprepared using4-((4-(4-amino-3-nitrophenyl)furan-2-yl)methyl)phthalazin-1(2H)-one(I-3.39.). MS (EI) for C₁₉H₁₆N₄O₂: 333 [M+H].

Intermediate I-5.40.4-((3′,4′-Diamino-5′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-3′,6-difluoro-5′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.40.). MS (EI) for C₂₁H₁₆F₂N₄O: 379 [M+H].

Intermediate I-5.41.4-((4′,5′-Diamino-2′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-2′,6-difluoro-5′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.56.). MS (EI) for C₂₁H₁₆F₂N₄O: 379 [M+H].

Intermediate I-5.42.4-((3′,4′-Diamino-2′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-2′,6-difluoro-3′-nitro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-3.42.). MS (EI) for C₂₁H₁₆F₂N₄O: 379 [M+H].

Intermediate I-5.44.4-(3-(5,6-Diaminopyridin-2-yl)-4-fluorobenzyl)phthalazin-1(2H)-one wasprepared using4-(3-(6-amino-5-nitropyridin-2-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(1-3.59.). MS (EI) for C₂₀H₁₆FN₅O: 362 [M+H].

Intermediate I-5.45.4-(3-(5,6-Diaminopyridin-3-yl)-4-fluorobenzyl)phthalazin-1 (2H)-one isprepared using4-(3-(6-amino-5-nitropyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(1-3.45.). MS (EI) for C₂₀H₁₆FN₅O: 362 [M+H].

Intermediate I-5.46.4-(3-(4,5-Diaminopyridin-2-yl)-4-fluorobenzyl)phthalazin-1 (2H)-one isprepared using4-(3-(4-amino-5-nitropyridin-2-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(1-3.61.). MS (EI) for C₂₀H₁₆FN₅O: 362 [M+H].

Intermediate I-5.47.4-(3-(5,6-Diamino-2-methylpyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one was prepared using4-(3-(6-amino-2-methyl-5-nitropyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(1-3.47.). MS (EI) for C₂₁H₁₈FN₅O: 376 [M+H].

Intermediate I-5.48.4-(3-(5,6-Diamino-4-methylpyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one is prepared using4-(3-(6-amino-4-methyl-5-nitropyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one (1-3.48.). MS (EI) for C₂₁H₁₈FN₅O: 376 [M+H].

Intermediate I-5.49.4-((3′,4′-Diamino-2-fluoro-[1,1′-biphenyl]-4-yl)methyl)phthalazin-1(2H)-onewas prepared using4-((4′-amino-2-fluoro-3′-nitro-[1,1′-biphenyl]-4-yl)methyl)phthalazin-1(2H)-one(1-3.49.). MS (EI) for C₂₁H₁₇FN₄O: 361 [M+H].

Example 1 Example 1.1. Methyl(5-{2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]phenyl}-1H-benzimidazol-2-yl)carbamate

A solution of4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.1.) (0.36 g, 1.00 mmol) and1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.21 g, 1.00 mmol)in acetic acid (5.0 mL) was stirred at 98° C. for 18 hours. Aftercooling the reaction mixture to room temperature it was diluted withwater (5 mL) and the pH was adjusted to 8 by the addition of 10N aqueoussodium hydroxide (8.6 mL), and then partitioned with ethyl acetate (100mL). The organic layer was separated, washed with saturated aqueoussodium bicarbonate (50 ml), brine (50 mL), dried over anhydrous sodiumsulfate and concentrated. The resulting crude was purified by gradientsilica gel flash chromatography (5-20% 7N ammonia in methanol in ethylacetate) to give methyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-H-benzimidazol-2-yl)carbamate(E-1.1.) (0.25 g, 57%). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 11.82(br s, 2H), 8.26 (d, 1H), 8.04 (d, 1H), 7.90 (t, 1H), 7.80 (t, 1H),7.54-7.46 (m, 2H), 7.44 (d, 1H), 7.26 (m, 1H), 7.20 (m, 2H), 4.34 (s,2H), 3.80 (s, 3H). MS (EI) for C₂₄H₁₈FN₅O₃: 444 [M+H].

Example E-1.2

Methyl(5-(3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one)(I-5.2.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.25 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.81 (t, 1H), 7.57 (m, 2H), 7.43 (m, 2H), 7.29(m, 2H), 7.20 (m, 1H), 4.35 (s, 2H), 3.77 (s, 3H). MS (EI) forC₂₄H₁₉N₅O₃: 426 [M+H].

Example E-1.3

Methyl(5-(2-chloro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-chloro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.3.). 1H-NMR (300 MHz, d₆-DMSO): 12.60 (s, 1H), 8.26 (d,1H), 8.04 (d, 1H), 7.92 (t, 1H), 7.82 (t, 1H), 7.49 (m, 2H), 7.45 (d,1H), 7.26-7.18 (m, 3H), 4.36 (s, 2H), 3.78 (s, 3H). MS (EI) forC₂₄H₁₈ClN₅O₃: 460 [M+H].

Example E-1.4

Methyl(5-(2-methyl-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-methyl-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.4.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.26 (d, 1H), 8.02(d, 1H), 7.89 (t, 1H), 7.82 (t, 1H), 7.45 (s, 1H), 7.42 (d, 1H),7.26-7.22 (m, 2H), 7.12 (d, 1H), 7.04 (d, 1H), 4.28 (s, 2H), 3.78 (s,3H), 2.42 (s, 3H). MS (EI) for C₂₅H₂₁N₅O₃: 440 [M+H].

Example E-1.5

Methyl(5-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-(trifluoro-methyl)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.5). 1H-NMR (300 MHz, d₆-DMSO): 12.60 (s, 1H), 8.26 (d,1H), 8.04 (d, 1H), 7.92 (t, 1H), 7.82 (t, 1H), 7.50 (m, 2H), 7.47 (d,1H), 7.26-7.18 (m, 3H), 4.35 (s, 2H), 3.78 (s, 3H). MS (EI) forC₂₅H₁₈F₃N₅O₃: 494 [M+H].

Example E-1.6

Methyl(5-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-(trifluoromethoxy)phenyl)-1H-benzoimidazol-2-yl)carbamate carbamate was prepared using4-((3′,4′-diamino-6-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.6.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.25 (d, 1H), 8.03(d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.45 (s, 1H), 7.36 (d, 1H), 7.26(s, 1H), 7.22 (d, 1H), 7.10 (d, 1H), 6.98 (d, 1H), 4.28 (s, 2H), 3.78(s, 3H). MS (EI) for C₂₅H₁₈F₃N₅O₄: 510 [M+H].

Example E-1.7

Methyl(5-(2-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.7.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), (d, 1H), 8.03 (d,1H), 7.88 (t, 1H), 7.82 (t, 1H), 7.44 (s, 1H), 7.39 (d, 1H), 7.26 (s,1H), 7.24 (d, 1H), 7.06 (d, 1H), 6.96 (d, 1H), 4.28 (s, 2H), 3.80 (s,3H). MS (EI) for C₂5H₂₁N₅O₄: 456 [M+H].

Example E-1.8

Methyl(5-(2-ethoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-ethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.8.). 1H-NMR (300 MHz, d₆-DMSO): 12.57 (s, 1H), 8.26 (d, 1H), 8.04(d, 1H), 7.89 (t, 1H), 7.82 (t, 1H), 7.43 (s, 1H), 7.37 (d, 1H), 7.26(s, 1H), 7.22 (d, 1H), 7.10 (d, 1H), 6.98 (d, 1H), 4.63 (q, 2H), 4.28(s, 2H), 3.79 (s, 3H), 1.58 (t, 3H). MS (EI) for C₂₆H₂₃N₅O₄: 470 [M+H].

Example E-1.9

Methyl(5-(2-(2-methoxyethoxy)-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-(2-methoxyethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.9.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.25 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.82 (t, 1H), 7.43 (s, 1H), 7.40 (d, 1H), 7.28(s, 1H), 7.22 (d, 1H), 7.11 (d, 1H), 6.96 (d, 1H), 4.30 (m, 2H), 4.28(s, 2H), 3.80 (s, 3H), 3.60 (m, 2H), 3.78 (s, 3H). MS (EI) forC₂₇H₂₅N₅O₅: 500 [M+H].

Example E-1.10

Methyl(5-(2-(difluoromethoxy)-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.10.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.26 (d, 1H), 8.03(d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.43 (m, 2H), 7.41 (d, 1H), 7.26(m, 1H), 7.22-7.12 (m, 3H), 4.35 (s, 2H), 3.78 (s, 3H). MS (EI) forC₂₅H₁₉F₂N₅O₄: 492 [M+H].

Example E-1.11

Methyl(5-(3-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-5-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.11.). 1H-NMR (300 MHz, d₆-DMSO): 12.60 (s, 1H), 8.24 (d, 1H), 8.04(d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.62 (s, 1H), 7.47-7.42 (m, 2H),7.31 (d, 1H), 7.26 (dd, 1H), 7.07 (d, 1H), 4.38 (s, 2H), 3.78 (s, 3H).MS (EI) for C₂₄H₁₈FN₅O₃: 444 [M+H].

Example E-1.12

Methyl(5-(4-fluoro-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-4-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.12.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.26 (d, 1H), 8.04(d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.48 (m, 2H), 7.45 (d, 1H), 7.30(m, 1H), 7.21 (m, 2H), 4.35 (s, 2H), 3.79 (s, 3H). MS (EI) forC₂₄H₁₈FN₅O₃: 444 [M+H].

Example E-1.13

Methyl(5-(2-fluoro-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.13.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.26 (d, 1H), 8.04(d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.52 (s, 1H), 7.45 (m, 2H), 7.22(m, 3H), 4.36 (s, 2H), 3.78 (s, 3H). MS (EI) for C₂₄H₁₈FN₅O₃: 444 [M+H].

Example E-1.14

Methyl(5-(2,4-difluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-4,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.14.) 1H-NMR (300 MHz, d₆-DMSO): 12.60 (s, 1H), 8.26 (d, 1H), 8.04(d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.48 (m, 2H), 7.45 (d, 1H), 7.21(d, 1H), 6.84 (m, 1H), 4.35 (s, 2H), 3.78 (s, 3H). MS (EI) forC₂₄H₁₇F₂N₅O₃: 462 [M+H].

Example E-1.15

Methyl(5-(2,3-difluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-5,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.15.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.25 (d,1H), 8.04 (d, 1H), 7.92 (t, 1H), 7.83 (t, 1H), 7.49 (m, 3H), 7.23 (d,1H), 7.08 (m, 1H), 4.35 (s, 2H), 3.78 (s, 3H). MS (EI) for C₂₄H₁₇F₂N₅O₃:462 [M+H].

Example E-1.16

Methyl(5-(3-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-5-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.16.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d, 1H), 8.03(d, 1H), 7.89 (t, 1H), 7.82 (t, 1H), 7.43 (s, 1H), 7.36 (d, 1H), 7.21(d, 1H), 7.20 (s, 1H), 7.18 (s, 1H), 6.98 (d, 1H), 4.28 (s, 2H), 3.76(3H), 3.70 (s, 3H). MS (EI) for C₂₅H₂₁N₅O₄: 456 [M+H].

Example E-1.17

Methyl(5-(4-methoxy-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-4-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.17.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.2 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.82 (t, 1H), 7.44 (s, 1H), 7.38 (d, 1H), 7.26(s, 1H), 7.19-7.12 (m, 2H), 6.98 (d, 1H), 4.28 (s, 2H), 3.78 (s, 3H),3.64 (s, 3H). MS (EI) for C₂₅H₂₁N₅O₄: 456 [M+H].

Example E-1.18

Methyl(5-(2-methoxy-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-2-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.18.). 1H-NMR (300 MHz, d₆-DMSO): 12.57 (s, 1H), 8.25 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.82, (t, 1H), 7.56 (s, 1H), 7.42 (d, 1H), 7.23(m, 2H), 7.08 (m, 2H), 4.36 (s, 2H), 3.70 (s, 3H), 3.30 (s, 3H). MS (EI)for C₂₅H₂₁N₅O₄: 456 [M+H].

Example E-1.19

Methyl (5-(2,3-dimethoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-5,6-dimethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.1.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.82, (t, 1H), 7.44 (s, 1H), 7.38 (d, 1H), 7.22(s, 1H), 6.98 (d, 1H), 6.88 (s, 1H), 4.28 (s, 2H), 3.78 (s, 3H), 3.70(s, 6H). MS (EI) for C₂₆H₂₃N₅O₅: 486 [M+H].

Example E-1.20

Methyl (5-(2,4-dimethoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-4,6-dimethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.20.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d, 1H), 8.03(d, 1H), 7.88 (t, 1H), 7.82, (t, 1H), 7.44 (s, 1H), 7.37 (d, 1H), 7.27(s, 1H), 6.98 (d, 1H), 6.68 (s, 1H), 4.28 (s, 2H), 3.77 (s, 3H), 3.70(s, 3H), 3.68 (s, 3H). MS (EI) for C₂₆H₂₃N₅O₅: 486 [M+H].

Example E-1.21

Methyl(5-(2-fluoro-4-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.21.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.26 (d, 1H), 8.04(d, 1H), 7.88 (t, 1H), 7.82, (t, 1H), 7.52 (s, 1H), 7.48 (m, 2H), 7.24(m, 1H), 7.21 (d, 1H), 4.35 (s, 2H), 3.80 (s, 3H), 3.68 (s, 3H). MS (EI)for C₂₅H₂₀FN₅O₄: 474 [M+H].

Example E-1.22

Methyl(5-(4-fluoro-2-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-4-fluoro-6-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onecan (I-5.22.). MS (EI) for C₂₅H₂₀FN₅O₄: 474 [M+H].

Example E-1.23

Methyl(5-(2-fluoro-5-((5-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-8-fluorophthalazin-1(2H)-one(I-5.23.). MS (EI) for C₂₄H₁₇F₂N₅O₃: 462 [M+H].

Example E-1.24

Methyl(5-(2-fluoro-5-((6-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate is prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-7-fluorophthalazin-1(2H)-one(I-5.24.). MS (EI) for C₂₄H₁₇F₂N₅O₃: 462 [M+H].

Example E-1.25

Methyl(5-(2-fluoro-5-((7-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-fluorophthalazin-1(2H)-one(I-5.25.). MS (EI) for C₂₄H₁₇F₂N₅O₃: 462 [M+H].

Example E-1.26

Methyl(5-(2-fluoro-5-((8-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5-fluorophthalazin-1(2H)-one(I-5.26.). MS (EI) for C₂₄H₁₇F₂N₅O₃: 462 [M+H].

Example E-1.27

Methyl(5-(5-((5,8-difluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)carbamateis prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5,8-difluorophthalazin-1(2H)-one(I-5.27.). MS (EI) for C₂₄H₁₆F₃N₅O₃: 480 [M+H].

Example E-1.28

Methyl(5-(5-((6,7-difluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)carbamateis prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6,7-difluorophthalazin-1(2H)-one(I-5.28.). MS (EI) for C₂₄H₁₆F₃N₅O₃: 480 [M+H].

Example E-1.29

Methyl(5-(2-fluoro-5-((5-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate is prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-8-methylphthalazin-1(2H)-one(I-5.29.). MS (EI) for C₂₅H₂₀FN₅O₃: 458 [M+H].

Example E-1.30

Methyl(5-(2-fluoro-5-((6-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-7-methylphthalazin-1(2H)-one(I-5.30.). 1H NMR (300 MHz, d₆-DMSO): 12.47 (s, 1H), 8.13 (s, 1H), 7.88(d, 0.5H), 7.86 (s, 1H), 7.68 (d, 0.5H), 7.48 (m, 2H), 7.44 (d, 1H),7.27 (m, 1H), 7.21 (m, 2H), 4.30 (s, 2H), 3.76 (s, 3H), 2.46 (s, 3H). MS(EI) for C₂₅H₂₀FN₅O₃: 458 [M+H].

Example E-1.31

Methyl(5-(2-fluoro-5-((7-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate is prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-methylphthalazin-1(2H)-one(I-5.31.). 1H NMR (300 MHz, d₆-DMSO): 12.47 (s, 1H), 8.14 (d, 1H), 7.73(s, 1H), 7.60 (d, 1H), 7.48 (m, 2H), 7.45 (d, 1H), 7.26 (m, 1H), 7.19(m, 2H), 4.29 (s, 2H), 3.76 (s, 3H), 2.45 (s, 3H). MS (EI) forC₂₅H₂₀FN₅O₃: 458 [M+H].

Example E-1.32

Methyl(5-(5-((7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)carbamateis prepared using6-chloro-4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.32.). MS (EI) for C₂₄H₁₇ClFN₅O₃: 478 [M+H].

Example E-1.33

Methyl(5-(2-fluoro-5-((4-oxo-7-(trifluoromethyl)-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-H-benzoimidazol-2-yl)carbamateis prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoromethyl)phthalazin-1(2H)-one(I-5.33.). MS (EI) for C₂₅H₁₇F₄N₅O₃: 512 [M+H].

Example E-1.34

Methyl(5-(2-fluoro-5-((7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-H-benzoimidazol-2-yl)carbamateis prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-methoxyphthalazin-1(2H)-one(I-5.34.). MS (EI) for C₂₅H₂₀FN₅O₄: 474 [M+H].

Example E-1.35

Methyl(5-(2-fluoro-5-((4-oxo-7-(trifluoromethoxy)-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-H-benzoimidazol-2-yl)carbamateis prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoromethoxy)phthalazin-1(2H)-one(I-5.35.). MS (EI) for C₂₅H₁₇F₄N₅O₄: 528 [M+H].

Example E-1.36

Methyl(5-(5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6,7-dimethoxyphthalazin-1(2H)-one(I-5.36.). 1H NMR (300 MHz, d₆-DMSO): 12.54 (s, 1H), 7.58 (s. 1H),7.56-7.43 (m, 3H), 7.44, (s, 1H), 7.27 (m, 1H), 7.21 (m, 2H), 4.28 (s,2H), 3.94 (s, 6H), 3.78 (s, 3H). MS (EI) for C₂₆H₂₂FN₅O₅: 504 [M+H].

Example E-1.37

Methyl(5-(5-((6,8-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)carbamateis prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5,7-dimethoxyphthalazin-1(2H)-one(I-5.37.). MS (EI) for C₂₆H₂₂FN₅O₅: 504 [M+H].

Example E-1.538

Methyl(6-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)furan-2-yl)-1H-benzoimidazol-2-yl)carbamatecarbamate was prepared using4-((5-(3,4-diaminophenyl)furan-2-yl)methyl)phthalazin-1(2H)-one(I-5.38.). 1H NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.25 (d, 1H), 8.04(d, 1H), 7.89 (t, 1H), 7.81 (t, 1H), 7.52 (s, 1H), 7.44 (d, 1H), 7.18 (d1H), 6.64 (d, 1H), 6.30 (d, 1H), 4.38 (s, 2H), 3.76 (s, 3H). MS (EI) forC₂₂H₁₇N₅O₄: 416 [M+H].

Example E-1.39

Methyl(6-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)furan-3-yl)-1H-benzoimidazol-2-yl)carbamateis prepared using4-((4-(3,4-diaminophenyl)furan-2-yl)methyl)phthalazin-1(2H)-one(I-5.39.). MS (EI) for C₂₂H₁₇N₅O₄: 416 [M+H].

Example E-1.40

Methyl(7-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-5′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.40.). 1H-NMR (300 MHz, d₆-DMSO): 12.62 (s, 1H), 12.20 (s, 1H),11.50 (s, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.88 (t, 1H), 7.84 (t, 1H),7.54 (d, 1H), 7.44 (s, 1H), 7.27 (m, 1H), 7.23 (q, 1H), 7.08 (d, 1H),4.36 (s, 2H), 3.78 (s, 3H). MS (EI) for C₂₄H₁₇F₂N₅O₃: 462 [M+H].

Example E-1.41

Methyl(6-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((4′,5′-diamino-2′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.41.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.24 (d, 1H), 8.02(d, 1H), 7.89 (t, 1H), 7.82 (t, 1H), 7.41 (d, 1H), 7.33 (m, 2H), 7.24(m, 2H), 7.21 (t, 1H), 4.34 (s, 2H), 3.75 (s, 3H). MS (EI) forC₂₄H₁₇F₂N₅O₃: 462 [M+H].

Example E-1.42

Methyl(4-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-2′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.42.). 1H-NMR (300 MHz, d₆-DMSO): 12.57 (s, 1H), 8.23 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.80 (t, 1H), 7.41 (dd, 1H), 7.32 (m, 2H), 7.20(t, 1H), 7.00 (t, 1H), 4.34 (s, 2H), 3.76 (s, 3H). MS (EI) forC₂₄H₁₇F₂N₅O₃: 462 [M+H].

Example E-1.43

Methyl(7-chloro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((4′,5′-diamino-2′-chloro-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-4.1.). MS (EI) for C₂₄H₁₇ClFN₅O₃: 478 [M+H].

Example E-1.44

Methyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridin-2-yl)carbamatewas prepared using4-(3-(5,6-diaminopyridin-2-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-5.44.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.23 (d, 1H), 8.01(d, 1H), 7.84 (m, 1H), 7.80 (m, 3H), 7.47 (d, 1H), 7.36 (m, 1H), 7.22(dd, 1H), 4.36 (s, 2H), 3.76 (s, 3H). MS (EI) for C₂₃H₁₇FN₆O₃: 445[M+H].

Example E-1.45

Methyl(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamatecarbamate is prepared using4-(3-(5,6-diaminopyridin-3-yl)-4-fluorobenzyl)phthalazin-1 (2H)-one(I-5.45.). MS (EI) for C₂₃H₁₇FN₆O₃: 445 [M+H].

Example E-1.46

Methyl(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-c]pyridin-2-yl)carbamateis prepared using4-(3-(4,5-diaminopyridin-2-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-5.46.). MS (EI) for C₂₃H₁₇FN₆O₃: 445 [M+H].

Example E-1.47

Methyl(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-methyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamatewas prepared using4-(3-(5,6-diamino-2-methylpyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-5.47.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.25 (d, 1H), 8.01(d, 1H), 7.88 (t, 1H), 7.84 (m, 1H), 7.45 (s, 1H), 7.34 (m, 2H), 7.23(t, 1H), 4.34 (s, 2H), 3.74 (s, 3H), 2.24 (s, 3H). MS (EI) forC₂₄H₁₉FN₆O₃: 459 [M+H].

Example E-1.48

Methyl(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-7-methyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamateis prepared using4-(3-(5,6-diamino-4-methylpyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-5.48.). MS (EI) for C₂₄H₁₉FN₆O₃: 459 [M+H].

Example E-1.49

Methyl(6-(2-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-2-fluoro-[1,1′-biphenyl]-4-yl)methyl)phthalazin-1(2H)-one(I-5.49.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.26 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.83 (t, 1H), 7.49 (s, 1H), 7.41 (m, 2H),7.28-7.16 (m, 3H), 4.35 (s, 2H), 3.78 (s, 3H). MS (EI) forC₂₄H₁₈FN₅O₃:444 [M+H].

Example 2 Example 2.1. Ethyl(5-[2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]phenyl-1H-benzimidazol-2-yl)carbamate

A solution of4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.1.) (0.36 g, 1.00 mmol) and1,3-bis(ethoxycarbonyl)-2-methyl-2-thiopseudourea (R-5.1.) (0.23 g, 1.00mmol) in acetic acid (5.0 mL) was stirred at 98° C. for 18 hours. Aftercooling it to room temperature it was diluted with water (5 mL) and thepH was adjusted to 8 by the addition of 10N aqueous sodium hydroxide(8.6 mL). The white precipitate was collected by filtration, washed withwater and dried in vacuo. The crude product was triturated with amixture of ethyl acetate (45 mL) and ethanol (5 mL). The white solid wascollected by filtration to give ethyl(5-{2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]phenyl}-1H-benzimidazol-2-yl)carbamate (E-2.1.) (0.35 g, 76%). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s,1H), 11.77 (br s, 2H), 8.26 (d, 1H), 8.04 (d, 1H), 7.92 (t, 1H), 7.82(t, 1H), 7.50 (s, 1H), 7.49 (m, 1H), 7.45 (d, 1H), 7.27 (m, 1H), 7.21(d, 1H), 7.20 (t, 1H), 4.35 (s, 2H), 4.22 (q, 2H), 1.28 (t, 3H). 13C-NMR(d₆-DMSO): 159.47, 159.39, 156.23, 154.31, 148.08, 145.24, 134.58,134.53, 133.52, 131.52, 131.16, 129.24, 129.16, 129.07, 128.76, 127.91,127.76, 126.06, 125.62, 122.02, 116.25, 115.94, 61.32, 36.74, 14.41. MS(EI) for C₂₅H₂₀FN₅O₃: 458 [M+H].

Example E-2.2

Ethyl(5-(3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one)(I-5.2.). 1H-NMR (300 MHz, d₆-DMSO): 12.57 (s, 1H), 11.58 (s, 2H), 8.24(d, 1H), 8.01 (d, 1H), 7.88 (t, 1H), 7.80 (t, 1H), 7.58 (m, 2H), 7.42(m, 2H), 7.30 (m, 2H), 7.20 (m, 1H), 4.36 (s, 2H), 4.21 (q, 2H), 1.26(t, 3H). MS (EI) for C₂₅H₂₁N₅O₃: 440 [M+H].

Example E-2.3

Ethyl(5-(2-chloro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-chloro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.3.). 1H-NMR (300 MHz, d₆-DMSO): 12.60 (s, 1H), 8.25 (d,1H), 8.04 (d, 1H), 7.93 (t, 1H), 7.83 (t, 1H), 7.50 (m, 2H), 7.46 (d,1H), 7.26-7.18 (m, 3H), 4.35 (s, 2H), 4.22 (q, 2H), 1.28 (t, 3H). MS(EI) for C₂₅H₂₀ClN₅O₃: 474 [M+H].

Example E-2.4

Ethyl(5-(2-methyl-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-methyl-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.4.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d,1H), 8.02 (d, 1H), 7.88 (t, 1H), 7.82 (t, 1H), 7.45 (s, 1H), 7.41 (d,1H), 7.26-7.22 (m, 2H), 7.12 (d, 1H), 7.04 (d, 1H), 4.27 (s, 2H), 4.22(q, 2H), 2.45 (s, 3H), 1.28 (t, 3H). MS (EI) for C₂₆H₂₃N₅O₃: 454 [M+H].

Example E-2.5

Ethyl(5-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-(trifluoro-methyl)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.5.). 1H-NMR (300 MHz, d₆-DMSO): 12.60 (s, 1H), 8.26 (d, 1H), 8.04(d, 1H), 7.93 (t, 1H), 7.82 (t, 1H), 7.50 (m, 2H), 7.47 (d, 1H),7.26-7.18 (m, 3H), 4.35 (s, 2H), 4.21 (q, 2H), 1.28 (t, 3H). MS (EI) forC₂₆H₂₀F₃N₅O₃: 507 [M+H].

Example E-2.6

Ethyl(5-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-(trifluoromethoxy)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.6.). 1H-NMR (300 MHz, d₆-DMSO): 12.57 (s, 1H), 8.24 (d, 1H), 8.02(d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.44 (s, 1H), 7.37 (d, 1H), 7.26(s, 1H), 7.22 (d, 1H), 7.10 (d, 1H), 6.98 (d, 1H), 4.28 (s, 2H), 4.21(q, 2H), 1.28 (t, 3H). MS (EI) for C₂₆H₂₀F₃N₅O₄: 524 [M+H].

Example E-2.7

Ethyl(5-(2-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.7.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 11.55 (br s, 2H),8.24 (d, 1H), 8.02 (d, 1H), 7.88 (t, 1H), 7.83 (t, 1H), 7.44 (s, 1H),7.38 (d, 1H), 7.27 (s, 1H), 7.23 (d, 1H), 7.09 (d, 1H), 6.98 (d, 1H),4.28 (s, 2H), 4.22 (q, 2H), 3.70 (s, 3H), 1.27 (t, 3H). 13C-NMR(d₆-DMSO): 159.39, 154.77, 145.57, 133.45, 131.43, 130.87, 130.79,130.17, 129.17, 127.91, 126.02, 125.77, 111.88, 61.16, 59.77, 55.51,36.78, 20.78, 14.43, 14.09. MS (EI) for C₂₆H₂₃N₅O₄: 470 [M+H].

Example E-2.8

Ethyl(5-(2-ethoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-ethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.8.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 11.55 (br s, 1H),8.24 (d, 1H), 8.03 (d, 1H), 7.89 (t, 1H), 7.82 (t, 1H), 7.43 (s, 1H),7.37 (d, 1H), 7.26 (s, 1H), 7.22 (d, 1H), 7.10 (d, 1H), 6.98 (d, 1H),4.63 (q, 2H), 4.28 (s, 2H), 4.22 (q, 2H), 1.58 (t, 3H), 1.28 (t, 3H). MS(EI) for C₂₇H₂₅N₅O₄: 484 [M+H].

Example E-2.9

Ethyl(5-(2-(2-methoxyethoxy)-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-(2-methoxyethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.9.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.82 (t, 1H), 7.44 (s, 1H), 7.38 (d, 1H), 7.27(s, 1H), 7.23 (d, 1H), 7.12 (d, 1H), 6.97 (d, 1H), 4.30 (m, 2H), 4.28(s, 2H), 4.20 (q, 2H), 3.60 (m, 2H), 3.30 (s, 3H), 1.26 (s, 3H). MS (EI)for C₂₈H₂₇N₅O₅: 514 [M+H].

Example E-2.10

Ethyl(5-(2-(difluoromethoxy)-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.10.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.25 (d, 1H), 8.04(d, 1H), 7.89 (t, 1H), 7.82 (t, 1H), 7.44 (m, 2H), 7.42 (s, 1H), 7.26(m, 1.5H), 7.20-7.11 (m, 2.5H), 4.35 (s, 2H), 4.22 (q, 2H), 1.26 (t,3H). MS (EI) for C₂₆H₂₁F₂N₅O₄: 506 [M+H].

Example E-2.11

Ethyl(5-(3-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-5-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.11.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 11.63 (br s, 2H),8.25 (d, 1H), 8.03 (d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.62 (s, 1H),7.46 (s, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 7.27 (dd, 1H), 7.06 (d, 1H),4.38 (s, 2H), 4.23 (q, 2H), 1.26 (t, 3H). MS (EI) for C₂₅H₂₀FN₅O₃: 458[M+H].

Example E-2.12

Ethyl(5-(4-fluoro-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-4-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.12.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.25 (d, 1H), 8.03(d, 1H), 7.91 (t, 1H), 7.82 (t, 1H), 7.48 (m, 2H), 7.46 (d, 1H), 7.30(m, 1H), 7.20 (m, 2H), 4.35 (s, 2H), 4.21 (q, 2H), 1.28 (t, 3H). MS (EI)for C₂₅H₂₀FN₅O₃: 458 [M+H].

Example E-2.13

Ethyl(5-(2-fluoro-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.13.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.26 (d, 1H), 8.04(d, 1H), 7.92 (t, 1H), 7.83 (t, 1H), 7.52 (s, 1H), 7.46 (m, 2H), 7.24(m, 3H), 4.35 (s, 2H), 4.21 (q, 2H), 1.28 (t, 3H). MS (EI) forC₂₅H₂₀FN₅O₃: 458 [M+H].

Example E-2.14

Ethyl(5-(2,4-difluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-4,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.14.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.26 (d,1H), 8.03 (d, 1H), 7.91 (t, 1H), 7.82 (t, 1H), 7.48 (m, 2H), 7.44 (d,1H), 7.22 (d, 1H), 6.84 (m, 1H), 4.34 (s, 2H), 4.22 (q, 2H), 1.28 (t,3H). MS (EI) for C₂₅H₁₉F₂N₅O₃: 476 [M+H].

Example E-2.15

Ethyl(5-(2,3-difluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-5,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.15.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.26 (d, 1H), 8.04(d, 1H), 7.92 (t, 1H), 7.82 (t, 1H), 7.48 (m, 3H), 7.24 (d, 1H), 7.08(m, 1H), 4.35 (s, 2H), 4.22 (q, 2H), 1.28 (t, 3H). MS (EI) forC₂₅H₁₉F₂N₅O₃: 476 [M+H].

Example E-2.16

Ethyl(5-(3-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-5-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.16.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.82 (t, 1H), 7.43 (s, 1H), 7.36 (d, 1H), 7.23(d, 1H), 7.20 (s, 1H), 7.16 (s, 1H), 6.98 (d, 1H), 4.28 (s, 2H), 4.22,(q, 2H), 3.72 (s, 3H), 1.27 (t, 3H). MS (EI) for C₂₆H₂₃N₅O₄: 470 [M+H].

Example E-2.17

Ethyl(5-(4-methoxy-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-4-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.17.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.83 (t, 1H), 7.44 (s, 1H), 7.38 (d, 1H), 7.27(s, 1H), 7.19-7.12 (m, 2H), 7.00 (d, 1H), 4.28 (s, 2H), 4.22, (q, 2H),3.64 (s, 3H), 1.27 (t, 3H). MS (EI) for C₂₆H₂₃N₅O₄: 470 [M+H].

Example E-2.18

Ethyl(5-(2-methoxy-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-2-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.18.). 1H-NMR (300 MHz, d₆-DMSO): 12.53 (s, 1H), 8.27 (d, 1H), 8.03(d, 1H), 7.94 (t, 1H), 7.86, (t, 1H), 7.58 (s, 1H), 7.44 (d, 1H), 7.24(m, 2H), 7.08 (m, 2H), 4.36 (s, 2H), 4.22, (q, 2H), 3.30 (s, 3H), 1.28(t, 3H). MS (EI) for C₂₆H₂₃N₅O₄: 470 [M+H].

Example E-2.19

Ethyl(5-(2,3-dimethoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-5,6-dimethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.19.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d, 1H), 8.03(d, 1H), 7.87 (t, 1H), 7.82, (t, 1H), 7.44 (s, 1H), 7.37 (d, 1H), 7.22(s, 1H), 6.98 (d, 1H), 6.88 (s, 1H), 4.28 (s, 2H), 4.22, (q, 2H), 3.70(s, 6H), 1.27 (t, 3H). MS (EI) for C₂₇H₂₅N₅O₅: 500 [M+H].

Example E-2.20

Ethyl(5-(2,4-dimethoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-4,6-dimethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.20.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d, 1H), 8.03(d, 1H), 7.87 (t, 1H), 7.82, (t, 1H), 7.44 (s, 1H), 7.38 (d, 1H), 7.28(s, 1H), 6.98 (d, 1H), 6.68 (s, 1H), 4.28 (s, 2H), 4.22, (q, 2H), 3.70(s, 3H), 3.68 (s, 3H), 1.27 (t, 3H). MS (EI) for C₂7H₂₅N₅O₅: 500 [M+H].

Example E-2.21

Ethyl(5-(2-fluoro-4-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.21.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.26 (d, 1H), 8.04(d, 1H), 7.90 (t, 1H), 7.82, (t, 1H), 7.52 (s, 1H), 7.49 (m, 2H), 7.24(m, 1H), 7.22 (d, 1H), 4.35 (s, 2H), 4.21 (q, 2H), 3.68 (s, 3H), 1.28(t, 3H). MS (EI) for C₂₆H₂₂FN₅O₄: 488 [M+H].

Example E-2.22

Ethyl(5-(4-fluoro-2-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-4-fluoro-6-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onecan (I-5.22.). MS (EI) for C₂₆H₂₂FN₅O₄: 488 [M+H].

Example E-2.23

Ethyl (5-(2-fluoro-5-((5-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-8-fluorophthalazin-1(2H)-one(I-5.23.). MS (EI) for C₂₅H₁₉F₂N₅O₃: 476 [M+H]

Example E-2.24

Ethyl (5-(2-fluoro-5-((6-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate is prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-7-fluorophthalazin-1(2H)-one(I-5.24.). MS (EI) for C₂₅H₁₉F₂N₅O₃: 476 [M+H].

Example E-2.25

Ethyl (5-(2-fluoro-5-((7-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-fluorophthalazin-1(2H)-one(I-5.25.). 1H NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d, 1H), 7.96(m, 1H), 7.78 (m, 1H), 7.52-7.47 (m, 2H), 7.45 (d, 1H), 7.27 (m, 1H),7.20 (m, 2H), 4.36 (s, 2H), 4.20 (q, 2H), 1.27 (t, 3H). MS (EI) forC₂₅H₁₉F₂N₅O₃: 476 [M+H].

Example E-2.26

Ethyl (5-(2-fluoro-5-((8-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5-fluorophthalazin-1(2H)-one(I-5.26.). MS (EI) for C₂₅H₁₉F₂N₅O₃: 476 [M+H].

Example E-2.27

Ethyl(5-(5-((5,8-difluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5,8-difluorophthalazin-1(2H)-one(I-5.27.). MS (EI) for C₂₅H₁₈F₃N₅O₃: 494 [M+H].

Example E-2.28

Ethyl(5-(5-((6,7-difluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)carbamateis prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6,7-difluorophthalazin-1(2H)-one(I-5.28.). MS (EI) for C₂₅H₁₈F₃N₅O₃: 494 [M+H].

Example E-2.29

Ethyl (5-(2-fluoro-5-((5-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate is prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-8-methylphthalazin-1(2H)-one(I-5.29.). MS (EI) for C₂₆H₂₂FN₅O₃: 472 [M+H].

Example E-2.30

Ethyl (5-(2-fluoro-5-((6-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-7-methylphthalazin-1(2H)-one(I-5.30.). 1H NMR (300 MHz, d₆-DMSO): 12.46 (s, 1H), 11.56 (br s, 2H),8.12 (s, 1H), 7.90 (d, 0.5H), 7.86 (s, 1H), 7.65 (d, 0.5H), 7.48 (m,2H), 7.46 (d, 1H), 7.26 (m, 1H), 7.22 (m, 2H), 4.31 (s, 2H), 4.21 (q,2H), 2.46 (s, 3H), 1.27 (t, 3H). MS (EI) for C₂₆H₂₂FN₅O₃: 472 [M+H].

Example E-2.31

Ethyl(5-(2-fluoro-5-((7-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-methylphthalazin-1(2H)-one(I-5.31.). 1H NMR (300 MHz, d₆-DMSO): 12.46 (s, 1H), 11.58 (br s, 2H),8.13 (d, 1H), 7.74 (s, 1H), 7.60 (d, 1H), 7.48 (m, 2H), 7.46 (d, 1H),7.26 (m, 1H), 7.20 (m, 2H), 4.30 (s, 2H), 4.22 (q, 2H), 2.45 (s, 3H),1.26 (t, 3H). MS (EI) for C₂₆H₂₂FN₅O₃: 472 [M+H]. MS (EI) forC₂₆H₂₂FN₅O₃: 472 [M+H].

Example E-2.32

Ethyl(5-(5-((7-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)carbamateis prepared using6-chloro-4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one can (I-5.32.). MS (EI) for C₂₅H₁₉ClFN₅O₃: 492 [M+H].

Example E-2.33

Ethyl(5-(2-fluoro-5-((4-oxo-7-(trifluoromethyl)-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-H-benzoimidazol-2-yl)carbamateis prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoromethyl)phthalazin-1(2H)-one(I-5.33.). MS (EI) for C₂₆H₁₉F₄N₅O₃: 526 [M+H].

Example E-2.34

Ethyl(5-(2-fluoro-5-((7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamateis prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-methoxyphthalazin-1(2H)-one(I-5.34.). MS (EI) for C₂₆H₂₂FN₅O₄: 488 [M+H].

Example E-2.35

Ethyl(5-(2-fluoro-5-((4-oxo-7-(trifluoromethoxy)-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoromethoxy)phthalazin-1(2H)-one(I-5.35.). MS (EI) for C₂₆H₁₉F₄N₅O₄: 542 [M+H].

Example E-2.36

Ethyl(5-(5-((6,7-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6,7-dimethoxyphthalazin-1(2H)-one(I-5.36.). 1H NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 7.57 (s. 1H),7.54-7.44 (m, 3H), 7.43, (s, 1H), 7.27 (m, 1H), 7.20 (m, 2H), 4.28 (s,2H), 4.22 (q, 2H), 3.94 (s, 6H), 1.28 (t, 3H). MS (EI) for C₂7H₂₄FN₅O₅:518 [M+H].

Example E-2.37

Ethyl(5-(5-((6,8-dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)carbamateis prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5,7-dimethoxyphthalazin-1(2H)-one(I-5.37.). MS (EI) for C₂₇H₂₄FN₅O₅: 518 [M+H].

Example E-2.38

Ethyl(6-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)furan-2-yl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((5-(3,4-diaminophenyl)furan-2-yl)methyl)phthalazin-1(2H)-one(I-5.38.). 1H NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 11.63 (br s, 2H),8.26 (d, 1H), 8.04 (d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.54 (s, 1H),7.43 (d, 1H), 7.20 (d 1H), 6.65 (d, 1H), 6.30 (d, 1H), 4.39 (s, 2H),4.22 (q, 2H), 1.26 (t, 3H). MS (EI) for C₂₃H₁₉N₅O₄: 430 [M+H].

Example E-2.39

Ethyl(6-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)furan-3-yl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((4-(3,4-diaminophenyl)furan-2-yl)methyl)phthalazin-1(2H)-one(I-5.39.). MS (EI) for C₂₃H₁₉N₅O₄: 430 [M+H].

Example E-2.40

Ethyl(7-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-5′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.40.). 1H-NMR (300 MHz, d₆-DMSO): 12.61 (s, 1H), 12.20 (s, 1H),11.44 (s, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.90 (t, 1H), 7.84 (t, 1H),7.54 (d, 1H), 7.43 (s, 1H), 7.30 (m, 1H), 7.24 (q, 1H), 7.08 (d, 1H),4.36 (s, 2H), 4.24 (q, 2H), 1.28 (t, 3H). MS (EI) for C₂₅H₁₉F₂N₅O₃: 476[M+H].

Example E-2.41

Ethyl(6-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((4′,5′-diamino-2′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.41.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 11.97 (s, 1H),11.35 (s, 1H), 8.24 (d, 1H), 8.02 (d, 1H), 7.89 (t, 1H), 7.81 (t, 1H),7.41 (m, 1H), 7.32 (m, 2H), 7.24 (d, 1H), 7.20 (t, 1H), 4.34 (s, 2H),4.23 (q, 2H), 1.26 (t, 3H). MS (EI) for C₂₅H₁₉F₂N₅O₃: 476 [M+H].

Example E-2.42

Ethyl(4-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-2′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.42.). 1H-NMR (300 MHz, d₆-DMSO): 12.61 (s, 1H), 12.20 (s, 1H),11.42 (s, 1H), 8.25 (d, 1H), 8.04 (d, 1H), 7.91 (t, 1H), 7.88 (t, 1H),7.43 (d, 1H), 7.30 (m, 2H), 7.20 (t, 1H), 7.00 (t, 1H), 4.35 (s, 2H),4.23 (q, 2H), 1.28 (t, 3H). MS (EI) for C₂5H₁₉F₂N₅O₃: 476 [M+H].

Example E-2.58

Ethyl(7-chloro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((4′,5′-diamino-2′-chloro-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(1-4.1.). ¹H-NMR (300 MHz, d₆-DMSO): 12.62 (s, 1H), 12.19 (s, 1H), 11.41(s, 1H), 8.24 (d, 1H), 8.03 (d, 1H), 7.94-7.83 (m, 2H), 7.44 (d, 1H),7.32 (m, 2H), 7.21 (t, 1H), 6.98 (t, 1H), 4.35 (m, 2H), 4.24 (q, 2H),1.26 (t, 3H). MS (EI) for C₂₅H₁₉ClFN₅O₃: 492 [M+H].

Example E-2.44

Ethyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridin-2-yl)carbamatewas prepared using4-(3-(5,6-diaminopyridin-2-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-5.44.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 12 01 (br s, 1H),11.68 (br s, 1H), 8.24 (d, 1H), 8.11 (d, 1H), 7.83 (m, 1H), 7.82-7.78(m, 3H), 7.46 (d, 1H), 7.38 (m, 1H), 7.21 (dd, 1H), 4.34 (s, 2H), 4.23(q, 2H), 1.28 (t, 3H). MS (EI) for C²⁴H₁₉FN₆O₃: 459 [M+H].

Example E-2.45

Ethyl(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamateis prepared using4-(3-(5,6-diaminopyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-5.45.). MS (EI) for C₂₄H₁₉FN₆O₃: 459 [M+H].

Example E-2.46

Ethyl(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-c]pyridin-2-yl)carbamateis prepared using4-(3-(4,5-diaminopyridin-2-yl)-4-fluorobenzyl)phthalazin-1(2H)-one can(I-5.46.). MS (EI) for C₂₄H₁₉FN₆O₃: 459 [M+H].

Example E-2.47

Ethyl(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-methyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamatewas prepared using4-(3-(5,6-diamino-2-methylpyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-5.47.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 11.92 (br s, 1H),11.46 (br s, 1H), 8.21 (d, 1H), 8.01 (d, 1H), 7.87 (t, 1H), 7.82 (m,1H), 7.44 (s, 1H), 7.34 (m, 2H), 7.22 (t, 1H), 4.34 (s, 2H), 4.20 (q,2H), 2.24 (s, 3H), 1.28 (t, 3H). MS (EI) for C₂₅H₂₁FN₆O₃: 473 [M+H].

Example E-2.48

Ethyl(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-7-methyl-3H-imidazo[4,5-b]pyridin-2-yl)carbamateis prepared using4-(3-(5,6-diamino-4-methylpyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-5.48.). MS (EI) for C₂₅H₂₁FN₆O₃: 473 [M+H].

Example E-2.49

Ethyl(6-(2-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-2-fluoro-[1,1′-biphenyl]-4-yl)methyl)phthalazin-1(2H)-one(I-5.49.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.26 (d, 1H), 8.01(d, 1H), 7.88 (t, 1H), 7.82 (t, 1H), 7.50 (s, 1H), 7.42 (m, 2H), 7.26(t, 1H), 7.17 (m, 2H), 4.35 (s, 2H), 4.19 (q, 2H), 1.26 (t, 3H). MS (EI)for C₂₅H₂₀FN₅O₃: 458 [M+H].

Example 3 Example 3.1. 2-Methoxyethyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate

A solution of4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.1.) (0.18 g, 0.50 mmol) and1,3-bis(methoxyethoxycarbonyl)-2-methyl-2-thiopseudourea (R-5.2.) (0.15g, 0.50 mmol) in acetic acid (3.0 mL) was stirred at 98° C. for 18hours. After cooling the reaction mixture to room temperature it wasdiluted with water (5 mL) and the pH was adjusted to 8 by the additionof 10N aqueous sodium hydroxide (5.2 mL) and the residue was partitionedwith ethyl acetate (100 mL). The organic layer was separated, washedwith saturated aqueous sodium bicarbonate (2×25 mL) and brine (2×50 mL),dried over anhydrous sodium sulfate and concentrated. The resultingcrude was purified by gradient silica gel flash chromatography (5-20% 7Nammonia in methanol in ethyl acetate) to give 2-methoxyethyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate(E-3.1.) (0.18 g, 68%). 1H NMR (300 MHz, d₆-DMSO): 12.60 (s, 1H), 8.26(d, 1H), 8.04 (d, 1H), 7.93 (t, 1H), 7.82 (t, 1H), 4.51-7.47 (m, 2H),7.44 (d, 1H), 7.28 (m, 1H), 7.21-7.18 (m, 2H), 4.35 (s, 2H), 4.30 (m,2H), 3.59 (m, 2H), 3.24 (s, 3H). MS (EI) for C₂₆H₂₂FN₅O₄: 488 [M+H].

Example E-3.2

2-Methoxyethyl(7-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-5′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.55.). 1H-NMR (300 MHz, d₆-DMSO): 12.62 (s, 1H), 8.23 (d, 1H), 8.02(d, 1H), 7.90 (t, 1H), 7.80 (t, 1H), 7.51 (d, 1H), 7.29 (s, 1H), 7.22(m, 1H), 7.16 (q, 1H), 6.88 (d, 1H), 4.33 (s, 2H), 4.14 (m, 2H), 3.53(m, 2H), 3.23 (s, 3H). MS (EI) for C₂₆H₂₁F₂N₅O₄: 506 [M+H].

Example E-3.3

2-Methoxyethyl(6-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((4′,5′-diamino-2′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.56.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.24 (d, 1H), 8.02(d, 1H), 7.91 (t, 1H), 7.81 (t, 1H), 7.38 (d, 1H), 7.34 (m, 2H), 7.24(d, 1H), 7.20 (t, 1H), 4.34 (s, 2H), 4.30 (m, 2H), 3.58 (m, 2H), 3.26(s, 3H). MS (EI) for C₂₆H₂₁F₂N₅O₄: 506 [M+H].

Example E-3.4

2-Methoxyethyl(4-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using4-((3′,4′-diamino-2′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.57.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.23 (d, 1H), 8.02(d, 1H), 7.89 (t, 1H), 7.81 (t, 1H), 7.41 (d, 1H), 7.34 (m, 2H), 7.20(t, 1H), 7.00 (t, 1H), 4.33 (s, 2H), 4.30 (m, 2H), 3.60 m, (2H), 3.23(s, 3H). MS (EI) for C₂₆H₂₁F₂N₅O₄: 506 [M+H].

Example 4 Intermediate 64-(3-(2-amino-1H-benzoimidazol-6-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-6.)

A solution of4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-.5.1.) (0.54 g, 1.50 mmol) and cyanogen bromide (0.24 g, 2.25 mmol)in a mixture of ethanol-acetonitrile-water (2:1:1) (20 mL) was heated to76° C. for five hours. The reaction mixture was cooled to roomtemperature and partitioned with ethyl acetate (200 mL). The organiclayer was separated, washed with saturated aqueous sodium bicarbonate(2×50 mL) and brine (100 mL), dried over anhydrous sodium sulfate andconcentrated to give4-(3-(2amino-1H-benzoimidazol-6-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-6.). MS (EI) for C₂₂H₁₆FN₅O: 386 [M+H].

General Synthesis of Carbamate-Library (E-4.).

To solution of4-(3-(2-amino-1H-benzoimidazol-6-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-6.) (0.040 mg, 0.1 mmol) in anhydrous tetrahydrofuran (1.0 ml)1,1′-carbonyldiimidazole (0.021 g, 0.13 mmol) was added and the reactionmixture was stirred at 50° C. for eight hours, followed by the additionof alcohol (1.0 mmol, 10 eq.) and the reaction mixture was heated to 75°C. for four hours. The mixture was cooled to room temperature andpurified by preparative reverse phase HPLC chromatography(acetonitrile-water with 0.1% trifluoroacetic acid). The desired productwas collected, by concentrating the solvent to give title carbamate.

Example E-4.1

Propyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using 1-propanol. MS (EI) for C₂₆H₂₂FN₅O₃: 472 [M+H].

Example E-4.2

2-Fluoroethyl (5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using2-fluoroethan-1-ol. MS (EI) for C₂₅H₁₉F₂N₅O₃: 476 [M+H].

Example E-4.3

2,2-Difluoroethyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using2,2-difluoroethan-1-ol. MS (EI) for C₂₅H₁₈F₃N₅O₃: 494 [M+H].

Example E-4.4

2,2,2-Trifluoroethyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate was prepared using2,2,2-trifluoroethan-1-ol. MS (EI) for C₂₅H₁₇F₄N₅O₃: 512 [M+H].

Example E-4.5

Isopropyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using 2-propanol. MS (EI) for C₂₆H₂₂FN₅O₃: 472 [M+H].

Example E-4.6

sec-Butyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using 2-butanol. MS (EI) for C₂₇H₂₄FN₅O₃: 486 [M+H].

Example E-4.7

Cyclopropyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using cyclopropanol. MS (EI) for C₂₆H₂₀FN₅O₃: 470 [M+H].

Example E-4.8

Cyclobutyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using cyclobutanol. MS (EI) for C₂₇H₂₂FN₅O₃: 484 [M+H].

Example E-4.9

Cyclopentyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using cyclopentanol. MS (EI) for C₂₈H₂₄FN₅O₃: 498 [M+H].

Example E-4.10

Cyclohexyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using cyclohexanol. MS (EI) for C₂₉H₂₆FN₅O₃: 512 [M+H].

Example E-4.11

Oxetan-3-yl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using oxetan-3-ol. MS (EI) for C₂₆H₂₀FN₅O₄: 486 [M+H].

Example E-4.12

Tetrahydro-2H-pyran-4-yl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using tetrahydro-2H-pyran-4-ol. MS (EI) for C₂₈H₂₄FN₅O₄:514 [M+H].

Example E-4.13

1-Methylazetidin-3-yl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using 1-methylazetidin-3-ol. MS (EI) for C₂₇H₂₃FN₆O₃: 499[M+H].

Example E-4.14

1-Methylpiperidin-4-yl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using 1-methylpiperidin-4-ol. MS (EI) for C₂₉H₂₇FN₆O₃: 527[M+H].

Example E-4.15

2-(Dimethylamino)ethyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using 2-(dimethylamino) ethan-1-ol. MS (EI) forC₂₇H₂₅FN₆O₃: 501 [M+H].

Example E-4.16

2-(Diethylamino)ethyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using 2-(diethylamino)ethan-1-ol. MS (EI) forC₂₉H₂₉FN₆O₃:529 [M+H].

Example E-4.17

2-(Pyrrolidin-1-yl)ethyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using 2-(pyrrolidin-1-yl)ethan-1-ol. MS (EI) forC₂₉H₂₇FN₆O₃: 527 [M+H].

Example E-4.18

2-(4-Methylpiperazin-1-yl)ethyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzo[d]imidazol-2-yl)carbamatewas prepared using 2-(4-methylpiperazin-1-yl)ethan-1-ol. MS (EI) forC₃₀H₃₀FN₇O₃: 556 [M+H].

Example E-4.19

2-Morpholinoethyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using 2-morpholinoethan-1-ol. MS (EI) for C₂₉H₂₇FN₆O₄: 543[M+H].

Example E-4.20

2-(1-Methylpiperidin-4-yl)ethyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using 2-(1-methylpiperidin-4-yl)ethan-1-ol. MS (EI) forC₃₁H₃₁FN₆O₃: 555 [M+H].

Example E-4.21

3-(Dimethylamino)propyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using 3-(dimethylamino)propan-1-ol. MS (EI) forC₂₈H₂₇FN₆O₃: 515 [M+H].

Example E-4.22

Phenyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using phenol. MS (EI) for C₂₉H₂₀FN₅O₃: 506 [M+H].

Example E-4.23

Benzyl(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamatewas prepared using phenylmethanol. MS (EI) for C₃₀H₂₂FN₅O₃: 520 [M+H].

Example 5 Example 5.1.1-Ethyl-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzimidazol-2-yl)urea

A solution of4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.1.) (0.36 g, 1.00 mmol) and N,N′-bis[(ethylamino)-carbonyl]carbamimido thioic acid methyl ester (R-5.3.) (0.23 g, 1.00 mmol) inacetic acid (5.0 mL) was stirred at 98° C. for 18 hours. After coolingthe reaction mixture to room temperature it was diluted with water (5mL) and the pH was adjusted to 8 by the addition of 10N aqueous sodiumhydroxide (8.6 mL), and then partitioned with ethyl acetate (100 mL).The organic layer was separated, washed with saturated aqueous sodiumbicarbonate (50 ml), brine (50 mL), dried over anhydrous sodium sulfateand concentrated. The resulting crude was purified by gradient silicagel flash chromatography (5-20% 7N ammonia in methanol in ethyl acetate)to give1-ethyl-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzimidazol-2-yl)urea(E-5.1.) (0.30 g, 66%). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 11.64(s, 1H), 10.04 (s, 1H), 8.25 (d, 1H), 8.02 (d, 1H), 7.90 (t, 1H), 7.82(t, 1H), 7.43-7.43 (m, 3H), 7.27 (m, 1H), 7.22 (m, 2H), 4.35 (s, 2H),3.18 (m, 2H), 1.06 (t, 3H). MS (EI) for C₂₅H₂₁FN₆O₂: 457 [M+H].

Example E-5.2

1-Ethyl-3-(5-(3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using 4-((3′,4′-diamino-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one) (I-5.2.). MS (EI) for C₂₅H₂₂N₆O₂: 439 [M+H].

Example E-5.3

1-(5-(2-Chloro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-ethylureawas prepared using4-((3′,4′-diamino-6-chloro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.3.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.26 (d,1H), 8.04 (d, 1H), 7.92 (t, 1H), 7.82 (t, 1H), 7.49 (m, 2H), 7.45 (d,1H), 7.28-7.16 (m, 3H), 4.35 (s, 2H), (3.20 (m, 2H), 1.09 (t, 3H). MS(EI) for C₂₅H₂₁ClN₆O₂: 473 [M+H].

Example E-5.4

1-Ethyl-3-(5-(2-methyl-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-6-methyl-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.4.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.25 (d, 1H), 8.02(d, 1H), 7.89 (t, 1H), 7.83 (t, 1H), 7.44 (s, 1H), 7.41 (d, 1H),7.27-7.22 (m, 2H), 7.12 (d, 1H), 7.03 (d, 1H), 4.28 (s, 2H), 3.19 (m,2H), 2.43 (s, 3H), 1.08 (t, 3H). MS (EI) for C₂₆H₂₄N₆O₂: 453 [M+H].

Example E-5.5

1-Ethyl-3-(5-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)-1H-benzoimidazol-2-yl)urea was prepared using4-((3′,4′-diamino-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.5.). 1H-NMR (300 MHz, d₆-DMSO): 12.60 (s, 1H), 8.25 (d, 1H), 8.03(d, 1H), 7.92 (t, 1H), 7.82 (t, 1H), 7.50 (m, 2H), 7.46 (d, 1H),7.26-7.16 (m, 3H), 4.35 (s, 2H), 3.20 (m, 2H), 1.08 (t, 3H). MS (EI) forC₂₆H₂₁F₃N₆O₂: 506 [M+H].

Example E-5.6

1-Ethyl-3-(5-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-(trifluoromethoxy)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-6-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.6.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.25 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.83 (t, 1H), 7.43 (s, 1H), 7.36 (d, 1H), 7.26(s, 1H), 7.21 (d, 1H), 7.10 (d, 1H), 6.98 (d, 1H), 4.28 (s, 2H), 3.18(m, 2H), 1.07 (t, 3H). MS (EI) for C₂₆H₂₁F₃N₆O₃: 523 [M+H].

Example E-5.7

1-Ethyl-3-(5-(2-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-6-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.7.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 11.56 (s, 1H), 8.25(d, 1H), 8.02 (d, 1H), 7.87 (t, 1H), 7.82 (t, 1H), 7.45 (s, 1H), 7.38(d, 1H), 7.28 (s, 1H), 7.22 (d, 1H), 7.07 (d, 1H), 6.97 (d, 1H), 4.28(s, 2H), 3.70 (s, 3H), 3.20 (m, 2H), 1.08 (t, 3H). MS (EI) forC₂₆H₂₄N₆O₃: 469 [M+H].

Example E-5.8

1-(5-(2-Ethoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-ethylureawas prepared using4-((3′,4′-diamino-6-ethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.8.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.82 (t, 1H), 7.42 (s, 1H), 7.38 (d, 1H), 7.26(s, 1H), 7.21 (d, 1H), 7.08 (d, 1H), 6.97 (d, 1H), 4.62 (q, 2H), 4.28(s, 2H), 3.18 (m, 2H), 1.58 (t, 3H), 1.06 (t, 3H). MS (EI) forC₂₇H₂₆N₆O₃: 483 [M+H].

Example E-5.9

1-Ethyl-3-(5-(2-(2-methoxyethoxy)-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-6-(2-methoxyethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.9.). MS (EI) for C₂₈H₂₈N₆O₄: 513 [M+H].

Example E-5.10

1-(5-(2-(Difluoromethoxy)-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-ethylureawas prepared using4-((3′,4′-diamino-6-(difluoromethoxy)-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.10.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.26 (d, 1H), 8.04(d, 1H), 7.88 (t, 1H), 7.82 (t, 1H), 7.43 (m, 2H), 7.41 (s, 1H), 7.28(m, 1H), 7.22-7.12 (m, 3H), 4.35 (s, 2H), 3.0 (m, 2H), 1.06 (t, 3H). MS(EI) for C₂₆H₂₂F₂N₆O₃: 505 [M+H].

Example E-5.11

1-Ethyl-3-(5-(3-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-5-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.11.). 1H-NMR (300 MHz, d₆-DMSO): 12.60 (s, 1H), 8.26 (d,1H), 8.04 (d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.50 (m, 2H), 7.44 (d,1H), 7.24-7.19 (m, 3H), 4.35 (s, 2H), 3.18 (m, 2H), 1.06 (t, 3H). MS(EI) for C₂₅H₂₁FN₆O₂: 457 [M+H].

Example E-5.12

1-Ethyl-3-(5-(4-fluoro-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-4-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.12.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.26 (d,1H), 8.02 (d, 1H), 7.9 (t, 1H), 7.82 (t, 1H), 7.4 (m, 2H), 7.46 (d, 1H),7.30 (m, 1H), 7.19 (m, 2H), 4.35 (s, 2H), 3.20 (m, 2H), 1.09 (t, 3H). MS(EI) for C₂₅H₂₁FN₆O₂: 457 [M+H].

Example E-5.13

1-Ethyl-3-(5-(2-fluoro-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-2-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.13.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.26 (d,1H), 8.04 (d, 1H), 7.91 (t, 1H), 7.82 (t, 1H), 7.51 (s, 1H), 7.44 (m,2H), 7.26 (m, 3H), 4.35 (s, 2H),), 3.19 (m, 2H), 1.07 (t, 3H). MS (EI)for C₂₅H₂₁FN₆O₂: 457 [M+H].

Example E-5.14

1-(5-(2,4-Difluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-ethylureawas prepared using4-((3′,4′-diamino-4,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.14.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.26 (d,1H), 8.04 (d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.49 (m, 2H), 7.44 (d,1H), 7.21 (d, 1H), 6.85 (m, 1H), 4.35 (s, 2H), 3.20 (m, 2H), 1.06 (t,3H). MS (EI) for C₂₅H₂₀F₂N₆O₂: 475 [M+H].

Example E-5.15

1-(5-(2,3-Difluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-ethylureawas prepared using4-((3′,4′-diamino-5,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (I-5.15.). 1H-NMR (300 MHz, d₆-DMSO): 12.59 (s, 1H), 8.26 (d,1H), 8.04 (d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.49 (m, 3H), 7.2 (d,1H), 7.08 (m, 1H), 4.35 (s, 2H), 3.18 (m, 2H), 1.06 (t, 3H). MS (EI) forC₂₅H₂₀F₂N₆O₂: 475 [M+H].

Example E-5.16

1-Ethyl-3-(5-(3-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)urea was prepared using4-((3′,4′-diamino-5-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.16.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.26 (d, 1H), 8.02(d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.43 (s, 1H), 7.36 (d, 1H), 7.22(d, 1H), 7.20 (s, 1H), 7.16 (s, 1H), 6.98 (d, 1H), 4.28 (s, 2H), 3.72(s, 3H), 3.18 (m, 2H), 1.06 (t, 3H). MS (EI) for C₂₆H₂₄N₆O₃: 469 [M+H].

Example E-5.17

1-Ethyl-3-(5-(4-methoxy-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)urea was prepared using4-((3′,4′-diamino-4-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.17.). MS (EI) for C₂₆H₂₄N₆O₃: 469 [M+H].

Example E-5.18

1-Ethyl-3-(5-(2-methoxy-3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)urea was prepared using4-((3′,4′-diamino-2-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.18.). MS (EI) for C₂₆H₂₄N₆O₃: 469 [M+H].

Example E-5.19

1-(5-(2,3-Dimethoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-ethylureawas prepared using4-((3′,4′-diamino-5,6-dimethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.19.). MS (EI) for C₂₇H₂₆N₆O₄: 499 [M+H].

Example E-5.20

1-(5-(2,4-Dimethoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-ethylureawas prepared using4-((3′,4′-diamino-4,6-dimethoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.20.). 1H-NMR (300 MHz, d₆-DMSO): 12.56 (s, 1H), 8.24 (d, 1H), 8.02(d, 1H), 7.89 (t, 1H), 7.81, (t, 1H), 7.45 (s, 1H), 7.38 (d, 1H), 7.28(s, 1H), 6.97 (d, 1H), 6.68 (s, 1H), 4.28 (s, 2H), 3.70 (s, 3H), 3.68(s, 3H), 3.18 (m, 2H), 1.06 (t, 3H). MS (EI) for Formula: C₂₇H₂₆N₆O₄:499 [M+H].

Example E-5.21

1-Ethyl-3-(5-(2-fluoro-4-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-6-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.21.). MS (EI) for C₂₆H₂₃FN₆O₃: 487 [M+H].

Example E-5.22

1-Ethyl-3-(5-(4-fluoro-2-methoxy-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-4-fluoro-6-methoxy-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onecan (I-5.22.). MS (EI) for C₂₆H₂₃FN₆O₃: 487 [M+H].

Example E-5.23

1-Ethyl-3-(5-(2-fluoro-5-((5-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-8-fluorophthalazin-1(2H)-one(I-5.23.). MS (EI) for C₂₅H₂₀F₂N₆O₂: 475 [M+H].

Example E-5.24

1-Ethyl-3-(5-(2-fluoro-5-((6-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureais prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-7-fluorophthalazin-1(2H)-one (I-5.24.). MS (EI) for C₂₅H₂₀F₂N₆O₂: 475 [M+H].

Example E-5.25

1-Ethyl-3-(5-(2-fluoro-5-((7-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-fluorophthalazin-1(2H)-one(I-5.25.). MS (EI) for C₂₅H₂₀F₂N₆O₂: 475 [M+H].

Example E-5.26

1-Ethyl-3-(5-(2-fluoro-5-((8-fluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5-fluorophthalazin-1(2H)-one(I-5.26.). MS (EI) for C₂₅H₂₀F₂N₆O₂: 475 [M+H].

Example E-5.27

1-(5-(5-((5,8-Difluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)-3-ethylureais prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5,8-difluorophthalazin-1(2H)-one(I-5.27.). MS (EI) for C₂₅H₁₉F₃N₆O₂: 493 [M+H].

Example E-5.28

1-(5-(5-((6,7-Difluoro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)-3-ethylureais prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6,7-difluorophthalazin-1(2H)-one(I-5.28.). MS (EI) for C₂₅H₁₉F₃N₆O₂: 493 [M+H].

Example E-5.29

1-Ethyl-3-(5-(2-fluoro-5-((5-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureais prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-8-methylphthalazin-1(2H)-one (I-5.29.). MS (EI) for C₂₆H₂₃FN₆O₂: 471 [M+H].

Example E-5.30

1-Ethyl-3-(5-(2-fluoro-5-((6-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)urea was prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-7-methylphthalazin-1(2H)-one(I-5.30.). MS (EI) for C₂₆H₂₃FN₆O₂: 471[M+H].

Example E-5.31

1-Ethyl-3-(5-(2-fluoro-5-((7-methyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)urea was prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-methylphthalazin-1(2H)-one(I-5.31.). MS (EI) for C₂₆H₂₃FN₆O₂: 471 [M+H].

Example E-5.32

1-(5-(5-((7-Chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)-3-ethylureais prepared using6-chloro-4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-onecan (I-5.32.). MS (EI) for C₂₅H₂₀ClFN₆O₂: 491 [M+H].

Example E-5.33

1-Ethyl-3-(5-(2-fluoro-5-((4-oxo-7-(trifluoromethyl)-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureais prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoromethyl)phthalazin-1(2H)-one(I-5.33.). MS (EI) for C₂₆H₂₀F₄N₆O₂: 525 [M+H].

Example E-5.34

1-Ethyl-3-(5-(2-fluoro-5-((7-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureais prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-methoxyphthalazin-1(2H)-one(I-5.34.). MS (EI) for C₂₆H₂₃FN₆O₃: 487 [M+H].

Example E-5.35

1-Ethyl-3-(5-(2-fluoro-5-((4-oxo-7-(trifluoromethoxy)-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureais prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6-(trifluoromethoxy)phthalazin-1(2H)-one(I-5.35.). MS (EI) for C₂₆H₂₀F₄N₆O₃: 541 [M+H].

Example E-5.36

1-(5-(5-((6,7-Dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)-3-ethylureawas prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-6,7-dimethoxyphthalazin-1(2H)-one(I-5.36.). MS (EI) for C₂₇H₂₅FN₆O₄: 517 [M+H].

Example E-5.37

1-(5-(5-((6,8-Dimethoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol-2-yl)-3-ethylureais prepared using4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)-5,7-dimethoxyphthalazin-1(2H)-one(I-5.37.). MS (EI) for C₂₇H₂₅FN₆O₄: 517 [M+H].

Example E-5.38

1-Ethyl-3-(6-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)furan-2-yl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((5-(3,4-diaminophenyl)furan-2-yl)methyl)phthalazin-1(2H)-one(I-5.38.). MS (EI) for C₂₃H₂₀N₆O₃: 429 [M+H].

Example E-5.39

Ethyl-3-(6-(5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)furan-3-yl)-1H-benzoimidazol-2-yl)ureais prepared using4-((4-(3,4-diaminophenyl)furan-2-yl)methyl)phthalazin-1(2H)-one(I-5.39.). MS (EI) for: C₂₃H₂₀N₆O₃: 429 [M+H].

Example E-5.40

1-Ethyl-3-(7-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-5′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.40.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.24 (d, 1H), 8.02(d, 1H), 7.88 (t, 1H), 7.82 (t, 1H), 7.52 (d, 1H), 7.36 (s, 1H), 7.26(m, 1H), 7.18 (q, 1H), 7.00 (d, 1H), 4.33 (s, 2H), 3.18 (m, 2H), 1.09(t, 3H). MS (EI) for C₂₅H₂₀F₂N₆O₂: 475 [M+H].

Example E-5.41

1-Ethyl-3-(6-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureais prepared using4-((4′,5′-diamino-2′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.41.). MS (EI) for C₂₅H₂₀F₂N₆O₂: 475 [M+H].

Example E-5.42

1-Ethyl-3-(4-fluoro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-2′,6-difluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.42.). 1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 8.23 (d, 1H), 8.02(d, 1H), 7.86 (t, 1H), 7.80 (t, 1H), 7.43 (d, 1H), 7.33 (m, 1H), 7.22(d, 1H), 7.20 (t, 1H), 7.93 (t, 1H), 4.33 (s, 2H), 3.20 (m, 2H), 1.09(t, 3H). MS (EI) for C₂₅H₂₀F₂N₆O₂: 475 [M+H].

Example E-5.43

1-(7-Chloro-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-ethylureais prepared using4-((4′,5′-diamino-2′-chloro-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one (1-4.1.). MS (EI) for C₂₅H₂₀ClFN₆O₂: 491 [M+H].

Example E-5.44

1-Ethyl-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-imidazo[4,5-b]pyridin-2-yl)ureais prepared using4-(3-(5,6-diaminopyridin-2-yl)-4-fluoro-benzyl)phthalazin-1 (2H)-one(I-5.44.). MS (EI) for C₂₄H₂₀FN₇O₂: 458 [M+H].

Example E-5.45

1-Ethyl-3-(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)ureais prepared using4-(3-(5,6-diaminopyridin-3-yl)-4-fluoro-benzyl)phthalazin-1 (2H)-one(I-5.45.). MS (EI) for C₂₄H₂₀FN₇O₂: 458 [M+H].

Example E-5.46

1-Ethyl-3-(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3H-imidazo[4,5-c]pyridin-2-yl)ureais prepared using4-(3-(4,5-diaminopyridin-2-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-5.46.). MS (EI) for C₂₄H₂₀FN₇O₂: 458 [M+H].

Example E-5.47

1-Ethyl-3-(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-methyl-3H-imidazo[4,5-b]pyridin-2-yl)ureais prepared using4-(3-(5,6-diamino-2-methylpyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-5.47.). MS (EI) for C₂₅H₂₂FN₇O₂: 472 [M+H].

Example E-5.48

1-Ethyl-3-(5-(2-fluoro-5-((4-oxo-4,5-dihydrofuro[2,3-d]pyridazin-7-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureais prepared using4-(3-(5,6-diamino-4-methylpyridin-3-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-5.48). MS (EI) for C₂₅H₂₂FN₇O₂: 472 [M+H].

Example E-5.49

1-Ethyl-3-(6-(2-fluoro-4-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzo[d]imidazol-2-yl)ureawas prepared using4-((3′,4′-diamino-2-fluoro-[1,1′-biphenyl]-4-yl)methyl)phthalazin-1(2H)-one(I-5.49). MS (EI) for C₂₅H₂₁FN₆O₂: 457 [M+H].

Example 6

General Synthesis of Urea-Library (E-6.):

To solution of4-(3-(2-amino-1H-benzoimidazol-6-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(I-6.) (0.040 mg, 0.1 mmol) in anhydrous tetrahydrofuran (1.0 ml)1,1′-carbonyldiimidazole (0.021 g, 0.13 mmol) was added and the reactionmixture was stirred at 50° C. for eight hours, followed by the additionof amine (1.0 mmol, 10 eq.) and the reaction mixture was heated to 75°C. for four hours. It was cooled to room temperature and the residue waspurified by preparative reverse phase HPLC chromatography(acetonitrile-water with 0.1% trifluoroacetic acid). The desired productwas collected by concentrating the solvent to give title urea compound.

Example E-6.1

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-propylureawas prepared from 1-aminopropane. MS (EI) for C₂₆H₂₃FN₆O₂: 471 [M+H].

Example E-6.2

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(2-fluoroethyl)ureawas prepared using 2-fluoroethan-1-amine. MS (EI) for C₂₅H₂₀F₂N₆O₂: 475[M+H].

Example E-6.3

1-(2,2-Difluoroethyl)-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using 2,2-difluoroethan-1-amine. MS (EI) for C₂₅H₁₉F₃N₆O₂:493 [M+H].

Example E-6.4

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(2,2,2-trifluoroethyl)ureawas prepared using 2,2,2-trifluoroethan-1-amine. MS (EI) forC₂₅H₁₈F₄N₆O₂: 511 [M+H].

Example E-6.5

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-isopropylureawas prepared using 2-aminopropane. MS (EI) for C₂₆H₂₃FN₆O₂: 471 [M+H].

Example E-6.6

1-(sec-Butyl)-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)urea was prepared using 2-aminobutane. MS(EI) for C₂₇H₂₅FN₆O₂: 485 M+H].

Example E-6.7

1-Cyclopropyl-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)urea was prepared using cyclopropanamine.MS (EI) for C₂₆H₂₁FN₆O₂: 469 [M+H].

Example E-6.8

1-Cyclobutyl-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)urea was prepared using cyclobutanamine.MS (EI) for C₂₇H₂₃FN₆O₂: 483 [M+H].

Example E-6.9

1-Cyclopentyl-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)urea was prepared using cyclopentanamine.MS (EI) for C₂₈H₂₅FN₆O₂: 497 [M+H].

Example E-6.10

1-Cyclohexyl-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)urea was prepared using cyclohexanamine.MS (EI) for C₂₉H₂₇FN₆O₂: 511 [M+H].

Example E-6.11

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(oxetan-3-yl)ureawas prepared using 3-amino-oxetan. MS (EI) for C₂₆H₂₁FN₆O₃: 485 [M+H].

Example E-6.12

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)ureawas prepared using 4-amino-tetrahydro-2H-pyran. MS (EI) for C₂8H₂₅FN₆O₃:513 [M+H].

Example E-6.13

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(1-methylazetidin-3-yl)ureawas prepared using 3-amino-1-methy lazetidin. MS (EI) for C₂₇H₂₄FN₇O₂:498 [M+H].

Example E-6.14

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(1-methylpiperidin-4-yl)ureawas prepared using 4-amino-1-methylpiperidin. MS (EI) for C₂₉H₂₈FN₇O₂:526 [M+H].

Example E-6.15

1-(2-(Dimethylamino)ethyl)-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using N,N-dimethylethylene-diamine. MS (EI) forC₂₇H₂₆FN₇O₂: 500 [M+H].

Example E-6.16

1-(2-(Diethylamino)ethyl)-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using N,N-diethylethylenediamine. MS (EI) for C₂₉H₃₀FN₇O₂:528 [M+H].

Example E-6.17

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-H-benzoimidazol-2-yl)-3-(2-(pyrrolidin-1-yl)ethyl)ureawas prepared using 2-(pyrrolidin-1-yl)ethan-1-amine. MS (EI) forC₂₉H₂₈FN₇O₂: 526 [M+H].

Example E-6.18

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(2-(4-methylpiperazin-1-yl)ethyl)ureawas prepared using 2-(4-methylpiperazin-1-yl)ethan-1-amine. MS (EI) forC₃₀H₃₁FN₈O₂: 555 [M+H].

Example E-6.19

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(2-morpholinoethyl)ureawas prepared using 2-morpholinoethan-1-amine. MS (EI) for C₂₉H₂₈FN₇O₃:542 [M+H].

Example E-6.20

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(2-(1-methylpiperidin-4-yl)ethyl)ureawas prepared using 2-(1-methylpiperidin-4-yl)ethan-1-amine. MS (EI) forC₃₁H₃₂FN₇O₂: 554 [M+H].

Example E-6.21

1-(3-(Dimethylamino)propyl)-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using N,N-dimethylpropylenediamine. MS (EI) forC₂₈H₂₈FN₇O₂: 514 [M+H].

Example E-6.22

1-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-phenylureawas prepared using aniline. MS (EI) for C₂₉H₂₁FN₆O₂: 505 [M+H].

Example E-6.23

1-Benzyl-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using phenylmethanamine. MS (EI) for C₃₀H₂₃FN₆O₂: 519[M+H].

Example E-6.24

Methyl((5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamoyl)glycinatewas prepared using methyl glycinate. MS (EI) for C₂₆H₂₁FN₆O₄: 501 [M+H].

Example E-6.25

3-(5-(2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-1,1-dimethylureawas prepared using dimethylamine. MS (EI) for C₂₅H₂₁FN₆O₂: 457 [M+H].

Example E-6.26

1,1-Diethyl-3-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzoimidazol-2-yl)ureawas prepared using diethylamine. MS (EI) for C₂₇H₂₅FN₆O₂: 485 [M+H].

Example 7 Example 7.1.N-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzimidazol-2-yl)methanesulfonamide

A solution of4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.1.) (0.18 g, 0.50 mmol) andmethyl-N,N′-bis(methylsulfonyl)carbamimidothioate (R.5.4.) (0.13 g, 0.50mmol) in acetic acid (3.0 mL) was stirred at 98° C. for 18 hours. Aftercooling the reaction mixture to room temperature it was diluted withwater (5 mL) and the pH was adjusted to 8 by the addition of 10N aqueoussodium hydroxide (5.2 mL), and then partitioned with ethyl acetate (100mL), washed with brine (50 mL), dried over anhydrous sodium sulfate andconcentrated. The resulting crude was purified by gradient silica gelflash chromatography (5-20% 7N ammonia in methanol in ethyl acetate) togive N-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H-benzimidazol-2-yl) methanesulfonamide (E-7.1.) (0.17 g, 72%).1H-NMR (300 MHz, d₆-DMSO): 12.58 (s, 1H), 12.27 (s, 1H), 8.26 (d, 1H),8.04 (d, 1H), 7.90 (t, 1H), 7.82 (t, 1H), 7.55-752 (m, 3H), 7.23 (m,2H), 7.20 (t, 1H), 4.36 (s, 2H), 3.32 (s, 3H). MS (EI) for C₂₃H₁₈FN₅O₃S:464 [M+H].

Example 8 Example 8.1 Ethyl(5-[2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]phenyl-1H-benzimidazol-2-yl)carbamate

A solution of4-((3′,4′-diamino-6-fluoro-[1,1′-biphenyl]-3-yl)methyl)phthalazin-1(2H)-one(I-5.1.) (0.18 g, 0.50 mmol) and methyl N,N′-bis[(propyl)carbonyl]imidothiocarbamate (R-5.5.) (0.12 g, 0.50 mmol) in acetic acid (3.0 mL)was stirred at 98° C. for 18 hours. After cooling the reaction mixtureto room temperature it was diluted with water (5 mL) and the pH wasadjusted to 8 by the addition of 10N aqueous sodium hydroxide (5.2 mL),and then partitioned with ethyl acetate (100 mL), washed with brine (50mL), dried over anhydrous sodium sulfate and concentrated. The resultingcrude was purified by gradient silica gel flash chromatography (5-20% 7Nammonia in methanol in ethyl acetate) to giveN-(5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-H-benzimidazol-2-yl)butyramide(E-8.1.) (0.09 g, 38%). 1H-NMR (300 MHz, d₆-DMSO): 12.60 (s, 1H), 11.82(s, 2H), 8.26 (d, 1H), 8.04 (d, 1H), 7.88 (m, 2H), 7.46 (m, 3H), 7.26(m, 3H), 4.32 (s, 2H), 3.40 (dd, 2H), 2.24 (m, 2H), 0.96 (t, 3H). MS(EI) for C₂₆H₂₂FN₅O₂: 456 [M+H].

REAGENT SYNTHESIS Reagent R-1.1. 3-Bromo-4-(difluoromethoxy)benzaldehyde

To a mixture of 3-bromo-4-hydroxy-benzaldehyde (5.0 g, 24.88 mmol) andcesium carbonate (20.3 g, 62.20 mmol) in N,N-dimethylformamide (75 mL)was sodium chlorodifluoroacetate (7.6 g, 49.76 mmol) was added and thereaction mixture was stirred at 75° C. for 18 hours. It was partitionedwith ethyl acetate (250 mL) and water (100 mL), the organic phase waswashed with water (2×100 mL), 1M aqueous hydrochloric acid (2×150 mL)and brine (150 mL), dried over anhydrous sodium sulfate andconcentrated. The resulting crude was purified by gradient silica gelflash chromatography (0-25% ethyl acetate in hexanes) to give3-bromo-4-(difluoromethoxy) benzaldehyde (R-1.1.) (4.6 g, 74%). 1H-NMR(300 MHz, d₆-DMSO): 9.90 (s, 1H), 8.22 (d, 1H), 8.04 (dd, 1H), 7.56 (d,1H), 7.44 (t, 1H). MS (EI) for C₈H₅BrF₂O₂: 234 [M+H].

Reagent R-1.2. 5-Bromo-4-fluoro-2-methoxybenzaldehyde

To a solution of 4-fluoro-2-methoxybenzaldehyde (5.0 g, 32.45 mmol) inacetonitrile (100 mL) N-bromosuccinimide (7.22 g, 40.56 mmol) was addedand the reaction mixture was stirred at 70° C. under an atmosphere ofnitrogen for 18 hours. It was partitioned with ethyl acetate (350 mL)and water (100 mL), the organic phase was washed with 1M aqueoushydrochloric acid (2×150 mL) and brine (150 mL), dried over anhydroussodium sulfate and concentrated. The resulting crude was purified bygradient silica gel flash chromatography (0-25% ethyl acetate inhexanes) to give 5-bromo-4-fluoro-2-methoxybenzaldehyde (R-1.2.) (7.1 g,94%). 1H-NMR (300 MHz, d₆-DMSO): 10.28 (s, 1H), 7.98 (d, 1H), 6.86 (d,1H), 3.90 (s, 3H). MS (EI) for C₈H₆BrFO₂: 234 [M+H].

Reagent R-1.3. 5-Bromo-2-fluoro-4-methoxybenzaldehyde

To a solution of 2-fluoro-4-methoxybenzaldehyde (5.0 g, 32.45 mmol) inmethanol (50 mL) bromine (3.3 mL, 65.0 mmol)) was added dropwise at 0°C. and the reaction mixture was stirred for 18 hours. The mixture waspartitioned with ethyl acetate (350 mL) and water (100 mL), the organicphase was washed with water (2×150 mL), 2M aqueous sodium hydrogensulfite (2×150 mL and brine (150 mL), dried over anhydrous sodiumsulfate and concentrated. The resulting crude was purified by gradientsilica gel flash chromatography (0-25% ethyl acetate in hexanes) to give5-bromo-2-fluoro-4-methoxybenzaldehyde (R-1.3.) (6.6 g, 87%). 1H-NMR(300 MHz, d₆-DMSO): 10.20 (s, 1H), 8.04 (d, 1H), 6.72 (d, 1H), 3.98 (s,3H). MS (EI) for C₈H₆BrFO₂: 234 [M+H].

Reagent R-2.1. 2-Bromo-4-ethynyl-1-fluorobenzene

STEP 1. To a solution of 2-bromo-1-fluoro-4-iodobenzene (6.0 g, 20.0mmol), ethynyl-trimethylsilane (4.20 mL, 30.0 mmol) and piperidine (3.0mL, 30.0 mmol) in anhydrous tetrahydrofuran (100 mL) copper(I) iodide(0.38 g, 2.0 mmol) was added, followed by the addition ofbis(triphenylphosphine)palladium(II) dichloride (0.70 g, 1.0 mmol) andthe reaction mixture was stirred under an atmosphere of nitrogen for 18hours. The mixture was diluted with ethyl acetate (250 mL) and filteredthrough a pad of Celite, washed with an additional portion of ethylacetate (100 mL). The combined phases were washed with 1M aqueoushydrochloric acid (2×150 mL) and brine (150 mL), dried over anhydroussodium sulfate and concentrated. The resulting crude was purified bygradient silica gel flash chromatography (0-20% ethyl acetate inhexanes) to give ((4-bromo-3-fluorophenyl)ethynyl)trimethylsilane (5.0g, 92%).

STEP 2. To a solution of((4-bromo-3-fluorophenyl)ethynyl)trimethylsilane (5.0 g, 18.40 mmol) inmethanol (100 mL) was added potassium carbonate (7.64 g, 55.20 mmol) andthe reaction mixture was stirred at room temperature for 5 hours. Thesolvent was removed and the residue was partitioned with ethyl acetate(250 mL) and water (100 mL). The organic phase was washed with water(100 mL), 0.5 M aqueous hydrochloric acid (100 mL) and brine (100 mL),dried over anhydrous sodium sulfate and concentrated. The resultingcrude was purified by gradient silica gel flash chromatography (0-20%ethyl acetate in hexanes) to give 2-bromo-4-ethynyl-1-fluorobenzene (2b,R-2.1.) (3.40 g, 83%). 1H-NMR (300 MHz, d₆-DMSO): 7.78 (dd, 1H), 7.46(m, 1H), 7.32 (d, 1H), 4.28 (1H). MS (EI) for C₈H₄BrF: 199 [M+H].

Reagent R-3.1. N-(Quinolin-8-yl)benzamide

To a solution of 8-aminoquinoline (1.44 g, 10.0 mmol) and trimethylamine(2.8 mL, 20.0 mmol) in anhydrous tetrahydrofuran (7 mL) was added asolution of benzoyl chloride (1.3 mL, 11.0 mmol) in tetrahydrofuran (5mL) dropwise while maintain the temperature at 0° C. The reactionmixture was stirred for 18 hours at room temperature. It was partitionedwith ethyl acetate (250 mL) and water (100 mL). The organic phase waswashed with water (2×100 mL), and brine (100 mL), dried over anhydroussodium sulfate and concentrated. The resulting crude was purified bygradient silica gel flash chromatography (0-80% ethyl acetate inhexanes) to give N-(quinolin-8-yl)benzamide (1c, R-3.1.) (2.4 g, 96%).1H-NMR (300 MHz, d₆-DMSO): 10.70 (s, 1H), 9.01 (dd, 1H), 8.78 (dd, 1H),8.48 (d, 1H), 8.12-8.06 (m, 2H), 7.78 (dd, 1H), 7.66 (m, 5H).). MS (EI)for C₁₆H₁₂N₂O: 249 [M+H].

Reagent R-3.2

2,5-Difluoro-N-(quinolin-8-yl)benzamide was prepared using2,5-difluorobenzoyl chloride. MS (EI) for C₁₆H₁₀F₂N₂O: 285 [M+H].

Reagent R-3.3

2-Methyl-N-(quinolin-8-yl)benzamide is prepared using 2-methylbenzoylchloride. MS (EI) for C₁₇H₁₄N₂O: 263 [M+H].

Reagent R-3.4

3-Methyl-N-(quinolin-8-yl)benzamide was prepared using 3-methylbenzoylchloride. 1H NMR (300 MHz, d₆-DMSO): 10.65 (s, 1H), 9.02 (dd, 1H), 8.78(dd, 1H), 8.48 (dd, 1H), 7.88 (d, 2H), 7.76 (dd, 1H), 7.72 (m, 2H),7.60-7.48 (m, 2H), 2.48 (s, 3H). MS (EI) for C₁₇H₁₄N₂O: 263 [M+H].

Reagent R-3.5

4-Methyl-N-(quinolin-8-yl)benzamide was prepared using 4-methylbenzoylchloride. 1H NMR (300 MHz, d₆-DMSO): 10.67 (s, 1H), 9.02 (dd, 1H), 8.79(dd, 1H), 8.50 (dd, 1H), 8.00 (d, 2H), 7.76 (dd, 1H), 7.76-7.65 (m, 2H),7.46 (d, 2H), 2.4 (s, 3H). MS (EI) for C₁₇H₁₄N₂O: 263 [M+H].

Reagent R-3.6

4-Chloro-N-(quinolin-8-yl)benzamide is prepared using 4-chlorobenzoylchloride. MS (EI) for C₁₆H₁₁ClN₂O: 283 [M+H].

Reagent R-3.7

N-(Quinolin-8-yl)-4-(trifluoromethyl)benzamide is prepared using4-(trifluoromethyl)benzoyl chloride. MS (EI) for C₁₇H₁₁F₃N₂O: 317 [M+H].

Reagent R-3.8

4-methoxy-N-(quinolin-8-yl)benzamide is prepared using 4-methoxybenzoylchloride. MS (EI) for C₁₇H₁₄N₂O₂: 279 [M+H].

Reagent R-3.9

N-(quinolin-8-yl)-4-(trifluoromethoxy)benzamide is prepared using4-(trifluoromethoxy)benzoyl chloride. MS (EI) for C₁₇H₁₁F₃N₂O₂: 233[M+H].

Reagent R-3.10

3,5-dimethoxy-N-(quinolin-8-yl)benzamide is prepared using3,5-dimethoxybenzoyl chloride. MS (EI) for C₁₈H₁₆N₂O₃: 309 [M+H].

Reagent 4.1. 4′-Amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-carbaldehyde

A mixture of 3-bromo-4-fluorobenzaldehyde (2a) (2.45 g, 12.0 mmol),2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.20 g,12.0 mmol in a mixture of 1,4-dioxane (32.5 mL) and a solution ofpotassium carbonate (5.0 g, 36.0 mmol) in water (7.5 mL) was heated to98° C. and stirred until the reactants went into solution, then nitrogengas was bubbled through the solution for approximately thirty minutes,followed by the addition ofdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (120 mg, 0.15 mmol). The reaction mixture wasstirred under nitrogen atmosphere at 98° C. for 18 hours. It was cooledto room temperature and poured into water (250 mL). The precipitatedproduct was collected by filtration and washed successively with water,and then air-dried for thirty minutes. The resulting crude material wasdissolved in a mixture of ethyl acetate (300 mL) and tetrahydrofuran(150 mL) then anhydrous sodium sulfate (100 g) Celite (5 g) and silicagel (5 g) were added. The solution was left to age for twelve hours;then the solvent was concentrated. The precipitating solid was collectedby filtration, washed with a solution of 10% ethyl acetate in hexanesand air dried for thirty minutes. The resulting crude was dissolved inhot tetrahydrofuran (200 mL) and treated with charcoal, filtered througha pad of Celite, and the solvent was concentrated. The precipitatedproduct was collected by filtration and washed with heaxanes and airdried to give 4′-amino-6-fluoro-3′-nitro-[1,1′-biphenyl]-3-carbaldehyde(4, R-4.1.) (2.68 g, 86%) as an orange-brown solid. (TLC 30% ethylacetate in hexanes, Rf.: 0.70). 1H NMR (300 MHz, d₆-DMSO): 10.03 (s,1H), 8.22 (d, 1H), 8.12 (dd, 1H), 7.93 (m, 1H), 7.72-7.66 (m, 3H), 7.53(dd, 1H), 7.14 (d, 1H). 13C NMR (d₆-DMSO): 191.76, 164.23, 160.84,145.98, 135.77, 132.24, 127.39, 127.21, 125.36, 120.61, 119.74, 117.54,117.23. MS (EI) for C₁₃H₉FN₂O₃: 261 [M+H].

Reagent R-4. 2.4′-amino-5,6-difluoro-3′-nitro-[1,1′-biphenyl]-3-carbaldehyde

A mixture of 3-bromo-4,5-difluorobenzaldehyde (0.66 g, 3.00 mmol)2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.78 g,3.00 mmol) and potassium carbonate (1.24 g, 9.00 mmol) in a mixture of1,4-dioxane (12.5 mL) and water (2.5 mL) was purged with nitrogen gasand stirred 98° C. for 30 minutes followed by the addition of XPhos(Dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]2-yl)phosphine) (0.14g, 0.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.18 g, 0.15mmol) and the stirring was continued for 18 hours. It was cooled to roomtemperature and partitioned with ethyl acetate (200 mL) and 1M aqueoushydrochloric acid (100 ml). The organic layer was separated and washedwith 1M aqueous hydrochloric acid (100 ml) and brine (100 mL), driedover anhydrous sodium sulfate and concentrated. The resulting crude waspurified by gradient silica gel flash chromatography (5-75% ethylacetate in hexanes) to give4′-amino-5,6-difluoro-3′-nitro-[1,1′-biphenyl]-3-carbaldehyde (R-4.2.)(0.26 g, 32%). MS (EI) for C₁₃H₈F₂N₂O₃: 279 [M+H].

Reagent R-4.3. 4-(4-amino-3-nitrophenyl)furan-2-carbaldehyde

A mixture of 4-bromofuran-2-carbaldehyde (0.52 g, 3.00 mmol)2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.78 g,3.00 mmol) and potassium carbonate (1.24 g, 9.00 mmol) in a mixture of1,4-dioxane (12.5 mL) and water (2.5 mL) was purged with nitrogen gasand stirred 98° C. for 30 minutes followed by the addition ofdichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium (II)dichloromethane adduct (0.12 g, 0.15 mmol) and the stirring wascontinued for 18 hours. It was cooled to room temperature andpartitioned with ethyl acetate (200 mL) and 1M aqueous hydrochloric acid(100 ml). The organic layer was separated and washed with 1M aqueoushydrochloric acid (100 ml) and brine (100 mL), dried over anhydroussodium sulfate and concentrated. The resulting crude was purified bygradient silica gel flash chromatography (5-75% ethyl acetate inhexanes) to give 4-(4-amino-3-nitrophenyl)furan-2-carbaldehyde (R-4.3.)(0.40 g, 58%). MS (EI) for C₁₁H₈N₂O₄: 233 [M+H].

Reagent R-5.1. 1,3-Bis(ethoxycarbonyl)-2-methyl-2-thiopseudourea

STEP 1. To a suspension of 2-methyl-2-thiopseudourea hemi sulfate (4.56g, 16.40 mmol) and sodium bicarbonate (6.90 g, 82.00 mmol) in a mixtureof water (30 mL) and tetrahydrofuran (20 mL) was added dropwise asolution of ethyl chloroformate (3.30 mL, 34.40 mmol) in tetrahydrofuran(20 mL) at 0° C. in a course of two hours and was stirred overnight atroom temperature. The solvent was concentrated, and the residue waspartitioned with ethyl acetate (400 mL) and water (250 ml). The organiclayer was washed with water (2×150 mL) and brine (2×250 mL), dried overanhydrous sodium sulfate and concentrated to give1-ethoxycarbonyl-2-methyl-2-thiopseudourea (2.70 g). The resulting crudeproduct was used without further purification.

STEP 2. To a solution of 1-ethoxycarbonyl-2-methyl-2-thiopseudourea(2.70 g, 16.40 mmol) and triethylamine (4.60 mL, 32.80 mmol) intetrahydrofuran (30 mL) was added dropwise a solution of ethylchloroformate (1.70 mL, 17.40 mmol) in tetrahydrofuran (20 mL) at 0° C.and was stirred overnight at room temperature. It was partitioned withethyl acetate (400 mL) and 1M aqueous hydrochloric acid (150 ml). Theorganic layer was washed with 1M aqueous hydrochloric acid (2×150 mL)and brine (2×250 mL), dried over anhydrous sodium sulfate andconcentrated. The resulting crude product was purified by gradientsilica gel flash chromatography (hexane:ethyl acetate) to give1,3-bis(ethoxycarbonyl)-2-methyl-2-thiopseudourea (R-5.1.) as an oil(solidifies to white solid upon standing) (3.65 g, 95%). 1H-NMR (300MHz, d₆-DMSO): 11.13 (s, 1H), 4.10 (m, 4H), 2.28 (s, 3H), 1.22 (m, 6H).MS (EI) for C₈H₁₄N₂O₄S: 235 [M+H].

Reagent R-5.2

1,3-bis(methoxyethoxycarbonyl)-2-methyl-2-thiopseudourea was preparedusing 2-methoxyethyl chloroformate. 1H-NMR (300 MHz, d₆-DMSO): 11.14 (s,1H), 4.30 (m, 4H), 3.64 (m, 4H), 3.30 (s, 6H), 2.28 (s, 3H). MS (EI) forC₁₀H₁₈N₂O₆S: 295 [MH].

Reagent R-5.3

N,N′-bis[(ethylamino)-carbonyl] carbamimido thioic acid methyl ester wasprepared using ethyl isocyanate. 1H-NMR (300 MHz, d₆-DMSO): 11.12 (s,1H), 3.24 (q, 2H), 3.18 (q, 2H), 2.36 (s, 3H), 1.14 (m, 6H). MS (EI) forC₈H₁₆N₄O₂S: 233 [M+H].

Reagent R-5.4

Methyl-N,N-bis(methylsulfonyl)carbamimidothioate was prepared usingmethanesulfonyl chloride. 1H-NMR (300 MHz, d₆-DMSO): 11.16 (s, 1H), 2.48(s, 3H), 2.86 (s, 3H), 2.98 (s, 3H). MS (EI) for C₄H₁₀N₂O₄S₃: 247 [M+H].

Reagent R-5.5

Methyl N,N′-bis[(propyl)carbonyl] imidothiocarbamate was prepared usingbutanoyl chloride. 1H-NMR (300 MHz, d₆-DMSO): 11.14 (s, 1H), 2.48 (s,3H), 2.36 (m, 4H), 1.68 (m, 4H), 0.98 (m, 6H). MS [ESI] for C₁₀H₁₈N₂O₂S:231 [M+H].

Cmpd No. Structure Name Example 1. 1.

Methyl (5-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 2.

Methyl (5-(3-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate 3.

Methyl (5-(2-chloro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 4.

Methyl (5-(2-methyl-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 5.

Methyl (5-(5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 6.

Methyl (5-(5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)-2-(trifluoromethoxy)phenyl)-1H- benzoimidazol-2-yl)carbamate 7.

Methyl (5-(2-methoxy-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 8.

Methyl (5-(2-ethoxy-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 9.

Methyl (5-(2-(2-methoxyethoxy)- 5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 10.

Methyl (5-(2-(difluoromethoxy)- 5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 11.

Methyl (5-(3-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 12.

Methyl (5-(4-fluoro-3-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 13.

Methyl (5-(2-fluoro-3-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 14.

Methyl (5-(2,4-difluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 15.

Methyl (5-(2,3-difluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 16.

Methyl (5-(3-methoxy-5-((4-oxo- 3,4-dihydroplithalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 17.

Methyl (5-(4-methoxy-3-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 18.

Methyl (5-(2-methoxy-3-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 19.

Methyl (5-(2,3-dimethoxy-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 20.

Methyl (5-(2,4-dimethoxy-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 21.

Methyl (5-(2-fluoro-4-methoxy-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 22.

Methyl (5-(4-fluoro-2-methoxy-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoirnidazol-2-yl)carbamate 23.

Methyl (5-(2-fluoro-5-((5-fluoro- 4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 24.

Methyl (5-(2-fluoro-5-((6-fluoro- 4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 25.

Methyl (5-(2-fluoro-5-((7-fluoro- 4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 26.

Methyl (5-(2-fluoro-5-((8-fluoro- 4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 27.

Methyl (5-(5-((5,8-difluoro-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H- benzoimidazol-2-yl)carbamate 28.

Methyl (5-(5-((6,7-difluoro-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H- benzoimidazol-2-yl)carbamate 29.

Methyl (5-(2-fluoro-5-((5-methyl- 4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 30.

Methyl (5-(2-fluoro-5-((6-methyl- 4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 31.

Methyl (5-(2-fluoro-5-((7-methyl- 4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 32.

Methyl (5-(5-((7-chloro-4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H- benzoimidazol-2-yl)carbamate 33.

Methyl (5-(2-fluoro-5-((4-oxo-7- (trifluoromethyl)-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate34.

Methyl (5-(2-fluoro-5-((7- methoxy-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 35.

Methyl (5-(2-fluoro-5-((4-oxo-7- (trifluoromethoxy)-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate36.

Methyl (5-(5-((6,7-dimethoxy-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H- benzoimidazol-2-yl)carbamate 37.

Methyl (5-(5-((6,8-dimethoxy-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H- benzoimidazol-2-yl)carbamate 38.

Methyl (6-(5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)furan-2-yl)-1H-benzoimidazol-2-yl)carbamate 39.

Methyl (6-(5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)furan-3-yl)-1H-benzoimidazol-2-yl)carbamate 40.

Methyl (7-fluoro-5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 41.

Methyl (6-fluoro-5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 42.

Methyl (4-fluoro-5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 43.

Methyl (7-chloro-5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 44.

Methyl (5-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- imidazo[4,5-b]pyridin-2- yl)carbamate 45.

Methyl (6-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3H- imidazo[4,5-b]pyridin-2- yl)carbamate 46.

Methyl (6-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3H- imidazo[4,5-c]pyridin-2- yl)carbamate 47.

Methyl (6-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-methyl-3H- imidazo[4,5-b]pyridin-2- yl)carbamate 48.

Methyl (6-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-7-methyl-3H- imidazo[4,5-b]pyridin-2- yl)carbamate 49.

Methyl (6-(2-fluoro-4-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate Example 2. 1.

Ethyl (5-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 2.

Ethyl (5-(3-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)carbamate 3.

Ethyl (5-(2-chloro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 4.

Ethyl (5-(2-methyl-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 5.

Ethyl (5-(5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 6.

Ethyl (5-(5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)-2-(trifluoromethoxy)phenyl)-1H- benzoimidazol-2-yl)carbamate 7.

Ethyl (5-(2-methoxy-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 8.

Ethyl (5-(2-ethoxy-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 9.

Ethyl (5-(2-(2-methoxyethoxy)-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 10.

Ethyl (5-(2-(difluoromethoxy)-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 11.

Ethyl (5-(3-fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 12.

Ethyl (5-(4-fluoro-3-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 13.

Ethyl (5-(2-fluoro-3-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 14.

Ethyl (5-(2,4-difluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 15.

Ethyl (5-(2,3-difluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 16.

Ethyl (5-(3-methoxy-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 17.

Ethyl (5-(4-methoxy-3-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 18.

Ethyl (5-(2-methoxy-3-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 19.

Ethyl (5-(2,3-dimethoxy-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 20.

Ethyl (5-(2,4-dimethoxy-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 21.

Ethyl (5-(2-fluoro-4-methoxy-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 22.

Ethyl (5-(4-fluoro-2-methoxy-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 23.

Ethyl (5-(2-fluoro-5-((5-fluoro-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 24.

Ethyl (5-(2-fluoro-5-((6-fluoro-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 25.

Ethyl (5-(2-fluoro-5-((7-fluoro-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 26.

Ethyl (5-(2-fluoro-5-((8-fluoro-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 27.

Ethyl (5-(5-((5,8-difluoro-4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H- benzoimidazol-2-yl)carbamate 28.

Ethyl (5-(5-((6,7-difluoro-4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H- benzoimidazol-2-yl)carbamate 29.

Ethyl (5-(2-fluoro-5-((5-methyl-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 30.

Ethyl (5-(2-fluoro-5-((6-methyl-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 31.

Ethyl (5-(2-fluoro-5-((7-methyl-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 32.

Ethyl (5-(5-((7-chloro-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol- 2-yl)carbamate 33.

Ethyl (5-(2-fluoro-5-((4-oxo-7- (trifluoromethyl)-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate34.

Ethyl (5-(2-fluoro-5-((7-methoxy- 4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 35.

Ethyl (5-(2-fluoro-5-((4-oxo-7- (trifluoromethoxy)-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate36.

Ethyl (5-(5-((6,7-dimethoxy-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H- benzoimidazol-2-yl)carbamate 37.

Ethyl (5-(5-((6,8-dimethoxy-4- oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H- benzoimidazol-2-yl)carbamate 38.

Ethyl (6-(5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)furan-2-yl)-1H-benzoimidazol-2-yl)carbamate 39.

Ethyl (6-(5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)furan-3-yl)-1H-benzoimidazol-2-yl)carbamate 40.

Ethyl (7-fluoro-5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 41.

Ethyl (6-fluoro-5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 42.

Ethyl (4-fluoro-5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 43.

Ethyl (7-chloro-5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 44.

Ethyl (5-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- imidazo[4,5-b]pyridin-2- yl)carbamate 45.

Ethyl (6-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-3H- imidazo[4,5-b]pyridin-2- yl)carbamate 46.

Ethyl (6-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-3H- imidazo[4,5-c]pyridin-2- yl)carbamate 47.

Ethyl (6-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-5-methyl-3H- imidazo[4,5-b]pyridin-2- yl)carbamate 48.

Ethyl (6-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-7-methyl-3H- imidazo[4,5-b]pyridin-2- yl)carbamate 49.

Ethyl (6-(2-fluoro-4-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate Example 3. 1.

2-Methoxyethyl (5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 2.

2-Methoxyethyl (7-fluoro-5-(2- fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate3.

2-Methoxyethyl (6-fluoro-5-(2- fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate4.

2-Methoxyethyl (4-fluoro-5-(2- fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamateExample 4. 1.

Propyl (5-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 2.

2-Fluoroethyl (5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 3.

2,2-Difluoroethyl (5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 4.

2,2,2-Trifluoroethyl (5-(2-fluoro- 5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 5.

Isopropyl (5-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 6.

sec-Butyl (5-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 7.

Cyclopropyl (5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 8.

Cyclobutyl (5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 9.

Cyclopentyl (5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 10.

Cyclohexyl (5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 11.

Oxetan-3-yl (5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 12.

Tetrahydro-2H-pyran-4-yl (5-(2- fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate13.

1-Methylazetidin-3-yl (5-(2- fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 14.

1-Methylpiperidin-4-yl (5-(2- fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 15.

2-(Dimethylamino)ethyl (5-(2- fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 16.

2-(Diethylamino)ethyl (5-(2- fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 17.

2-(Pyrrolidin-1-yl)ethyl (5-(2- fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate18.

2-(4-Methylpiperazin-1-yl)ethyl (5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoldlimidazol-2-yl)carbamate 19.

2-Morpholinoethyl (5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 20.

2-(1-Methylpiperidin-4-yl)ethyl (5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate21.

3-(Dimethylamino)propyl (5-(2- fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate22.

Phenyl (5-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate 23.

Benzyl (5-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)carbamate Example 5. 1.

1-Ethyl-3-(5-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 2.

1-Ethyl-3-(5-(3-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)urea 3.

1-(5-(2-Chloro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-ethylurea 4.

1-Ethyl-3-(5-(2-methyl-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 5.

1-Ethyl-3-(5-(5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)-2-(trifluoromethyl)phenyl)-1H- benzoimidazol-2-yl)urea 6.

1-thyl-3-(5-(5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)-2-(trifluoromethoxy)phenyl)-1H- benzoimidazol-2-yl)urea 7.

1-Ethyl-3-(5-(2-methoxy-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 8.

1-(5-(2-Ethoxy-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-ethylurea 9.

1-Ethyl-3-(5-(2-(2- methoxyethoxy)-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 10.

1-(5-(2-(Difluoromethoxy)-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)-3-ethylurea 11.

1-Ethyl-3-(5-(3-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 12.

1-Ethyl-3-(5-(4-fluoro-3-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 13.

1-Ethyl-3-(5-(2-fluoro-3-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 14.

1-(5-(2,4-Difluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)-3-ethylurea 15.

1-(5-(2,3-Difluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)-3-ethylurea 16.

1-Ethyl-3-(5-(3-methoxy-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 17.

1-Ethyl-3-(5-(4-methoxy-3-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 18.

1-Ethyl-3-(5-(2-methoxy-3-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 19.

1-(5-(2,3-Dimethoxy-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)-3-ethylurea 20.

1-(5-(2,4-Dimethoxy-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)-3-ethylurea 21.

1-Ethyl-3-(5-(2-fluoro-4- methoxy-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 22.

1-Ethyl-3-(5-(4-fluoro-2- methoxy-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 23.

1-Ethyl-3-(5-(2-fluoro-5-((5- fluoro-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 24.

1-Ethyl-3-(5-(2-fluoro-5-((6- fluoro-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 25.

1-Ethyl-3-(5-(2-fluoro-5-((7- fluoro-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 26.

1-Ethyl-3-(5-(2-fluoro-5-((8- fluoro-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 27.

1-(5-(5-((5,8-Difluoro-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol- 2-yl)-3-ethylurea 28.

1-(5-(5-((6,7-Difluoro-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol- 2-yl)-3-ethylurea 29.

1-Ethyl-3-(5-(2-fluoro-5-((5- methyl-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 30.

1-Ethyl-3-(5-(2-fluoro-5-((6- methyl-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 31.

1-Ethyl-3-(5-(2-fluoro-5-((7- methyl-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 32.

1-(5-(5-((7-Chloro-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H-benzoimidazol- 2-yl)-3-ethylurea 33.

1-Ethyl-3-(5-(2-fluoro-5-((4-oxo- 7-(trifluoromethyl)-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 34.

1-Ethyl-3-(5-(2-fluoro-5-((7- methoxy-4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 35.

1-Ethyl-3-(5-(2-fluoro-5-((4-oxo- 7-(trifluoromethoxy)-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 36.

1-(5-(5-((6,7-Dimethoxy-4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H- benzoimidazol-2-yl)-3-ethylurea 37.

1-(5-(5-((6,8-Dimethoxy-4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)-2-fluorophenyl)-1H- benzoimidazol-2-yl)-3-ethylurea 38.

1-Ethyl-3-(6-(5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)furan-2-yl)-1H- benzoimidazol-2-yl)urea 39.

1-Ethyl-3-(6-(5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)furan-3-yl)-1H- benzoimidazol-2-yl)urea 40.

1-Ethyl-3-(7-fluoro-5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 41.

1-Ethyl-3-(6-fluoro-5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 42.

1-Ethyl-3-(4-fluoro-5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 43.

1-(7-Chloro-5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)-3-ethylurea 44.

1-Ethyl-3-(5-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- imidazo[4,5-b]pyridin-2-yl)urea 45.

1-Ethyl-3-(6-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3H- imidazo[4,5-b]pyridin-2-yl)urea 46.

1-Ethyl-3-(6-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-3H- imidazo[4,5-c]pyridin-2-yl)urea 47.

1-Ethyl-3-(6-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-methyl-3H- imidazo[4,5-b]pyridin-2-yl)urea 48.

1-Ethyl-3-(5-(2-fluoro-5-((4-oxo- 4,5-dihydrofuro[2,3-d]pyridazin-7-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 49.

1-Ethyl-3-(6-(2-fluoro-4-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzo[d]imidazol-2-yl)urea Example 6. 1.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-propylurea 2.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(2- fluoroethyl)urea 3.

1-(2,2-Difluoroethyl)-3-(5-(2- fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 4.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(2,2,2- trifluoroethyl)urea 5.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3- isopropylurea 6.

1-(sec-Butyl)-3-(5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 7.

1-Cyclopropyl-3-(5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 8.

1-Cyclobutyl-3-(5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 9.

1-Cyclopentyl-3-(5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 10.

1-Cyclohexyl-3-(5-(2-fluoro-5- ((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 11.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(oxetan-3- yl)urea 12.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3- (tetrahydro-2H-pyran-4-yl)urea 13.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(1- methylazetidin-3-yl)urea 14.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(1- methylpiperidin-4-yl)urea 15.

1-(2-(Dimethylamino)ethyl)-3-(5- (2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 16.

1-(2-(Diethylamino)ethyl)-3-(5- (2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 17.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(2- (pyrrolidin-1-yl)ethyl)urea 18.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(2-(4- methylpiperazin-1-yl)ethyl)urea 19.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(2- morpholinoethyl)urea 20.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-(2-(1- methylpiperidin-4-yl)ethyl)urea 21.

1-(3-(Dimethylamino)propyl)-3- (5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 22.

1-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-3-phenylurea 23.

1-Benzyl-3-(5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea 24.

Methyl ((5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2- yl)carbamoyl)glycinate 25.

3-(5-(2-Fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)-1,1- dimethylurea 26.

1,1-Diethyl-3-(5-(2-fluoro-5-((4- oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzoimidazol-2-yl)urea Example 7. 1.

N-(5 -(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-1-yl)methyl)phenyl)-1H- benzimidazol-2-yl) methanesulfonamide Example 8.1.

N-(5-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazin-1- yl)methyl)phenyl)-1H-benzoimidazol-2-yl)butyramide

Example 9 PARP1 Enzymatic Activity Inhibition: Determination of IC50Values for Selected Compounds

The half maximal inhibitory concentration (IC50) with respect to PARP1inhibition was determined for each test compound by using Trevigen's HTUniversal PARP Assay Kit, according to the manufacturer's protocol(Cat#4677-096-K, Gaithersburg, Md.). This assay measures theincorporation of biotinylated poly(ADP-ribose) onto histone proteins ina 96-well strip well format. This assay is ideal for the determinationof IC50 values of known or suspected PARP inhibitors. Briefly, stocksolutions of each test compound were prepared in DMSO. Histone stripwells were incubated for 30 minutes at room temperature with 50 l/wellof 1×PARP Buffer to rehydrate the histones. Serial dilutions of eithertest compound were added to appropriate wells. Diluted PARP enzyme (0.5Unit/well) was then added to the wells containing compounds, andincubated for 10 minutes at room temperature. Subsequently, 25 μl of1×PARP Cocktail, containing activated DNA, was distributed into eachwell. Three types of control wells were also analyzed; i. A negativecontrol without PARP was prepared to determine background absorbance.ii. An activity control for PARP Inhibitor Study: 0.5 Unit/well PARP-HSAwithout inhibitors. These wells provided the 100% activity referencepoint. iii. And a PARP Standard Curve: Serial dilution of the PARP-HASstandard were prepared in cold microtubes with IX PARP Buffer such thatthe total activity is 1 Unit/25 μl, 0.5 Units/25 μl, 0.25 Units/25 μl,0.1 Units/25 μl, 0.05 Units/25 μl, 0.025 Units/25 μl, and 0.01 Units/25μl. 25 μl of each standard was added to triplicate wells. Following a 60minutes incubation at room temperature, the strip wells were washedtwice with 1×PBS+0.1% Triton X-100, and twice with IX PBS. For activitydetection, 50 μl per well of diluted Strep-HRP was added, and thenincubated at room temperature for 60 minutes. Subsequently, 50 μl perwell of pre-warmed TACS-Sapphire™ colorimetric substrate was addedfollowed by a 15 minutes incubation, in the dark, at room temperature.The reactions were then stopped by adding 50 μl per well of 0.2M HCl or5% Phosphoric Acid and read the absorbance at 450 nm.

The IC50 values were determined by performing non-linear regressionanalysis fitting velocities and the logarithm of inhibitorconcentrations to a sigmoidal dose response with a variable slope modelusing the GraphPad Prism 6.0 software.

PARP 2 Enzymatic Activity Inhibition: Determination of IC50 Values forSelected Compounds

The half maximal inhibitory concentration (IC50) with respect to PARP2inhibition was determined for each test compound by using BPS BiosciencePARP2 Assay Kit, according to the manufacturer's protocol (Cat#80552,San Diego, Calif.). This assay measures the incorporation ofbiotinylated poly(ADP-ribose) onto histone proteins in a 96-well stripwell format. This assay is ideal for the determination of IC50 values ofknown or suspected PARP inhibitors. Briefly, stock solutions of eachtest compound were prepared in DMSO. Histone strip wells were incubatedfor 30 minutes at room temperature with 50 l/well of 1×PARP Buffer torehydrate the histones. Serial dilutions of either test compound wereadded to appropriate wells. Diluted PARP enzyme (0.5 Unit/well) was thenadded to the wells containing compounds, and incubated for 10 minutes atroom temperature. Subsequently, 25 μl of 1×PARP Cocktail, containingactivated DNA, was distributed into each well. Three types of controlwells were also analyzed; i. A negative control without PARP wasprepared to determine background absorbance. ii. An activity control forPARP Inhibitor Study: 0.5 Unit/well PARP-HSA without inhibitors. Thesewells provided the 100% activity reference point. iii. And a PARPStandard Curve: Serial dilution of the PARP-HAS standard were preparedin cold microtubes with 1×PARP Buffer such that the total activity is 1Unit/25 μl, 0.5 Units/25 μl, 0.25 Units/25 μl, 0.1 Units/25 μl, 0.05Units/25 μl, 0.025 Units/25 μl, and 0.01 Units/25 μl. 25 μl of eachstandard was added to triplicate wells. Following a 60 minutesincubation at room temperature, the strip wells were washed twice withIX PBS+0.1% Triton X-100, and twice with IX PBS. For activity detection,50 μl per well of diluted Strep-HRP was added, and then incubated atroom temperature for 60 minutes. Subsequently, 50 μl per well ofpre-warmed TACS-Sapphire™ colorimetric substrate was added followed byal 5 minutes incubation, in the dark, at room temperature. The reactionswere then stopped by adding 50 μl per well of 0.2M HCl or 5% PhosphoricAcid and read the absorbance at 450 nm.

The IC50 values were determined by performing non-linear regressionanalysis fitting velocities and the logarithm of inhibitorconcentrations to a sigmoidal dose response with a variable slope modelusing the GraphPad Prism 6.0 software. PARP2 inhibition by Ex. 1.1 is0.05 nM.

Trapping of PARP-DNA Complexes Formation Assay

Trapping PARP on damaged DNA has recently been proposed as a mechanismaccounting for the cytotoxicity of many PARP inhibitors. Using acellular Western Blot assay to measure PARP trapping on damaged DNA, weexamined chromatin-bound PARP1. To prepare chromatin-bound subcellularfraction, semiconfluent MDA-MB-436 human breast cancer cells with 10 mLmedium in 10 cm dish were exposed to various concentrations of the drugsfor 4 hours. Cells were then collected and fractionated using aSubcellular Protein Fractionation Kit from Thermo Scientific (78840)following the manufacturer's instructions. Immunoblotting was carriedout using standard procedures. Histone H3 was used as positive markersfor chromatin-bound fractions and as loading control. Topoisomerase 1was used as positive markers for soluble nuclear fractions and asloading control. Rabbit polyclonal anti-PARP1 antibody (#9542) waspurchased from cell signaling technology. Rabbit polyclonal anti-histoneH3 antibody (#4499) was from cell signaling technology. Mouse monoclonalanti-topoisomerase I antibody [23B11] was purchased from Abcam.Secondary antibodies were horseradish peroxidase (HRP)-conjugatedantibodies to rabbit immunoglobulin G (IgG; GE Healthcare).

Tubulin Polymerization Assay

The high-throughput screening-tubulin polymerization assay kit(Cytoskeleton, Cat. #BK011P) is an economical one step procedure fordetermining the effects of drugs or proteins on tubulin polymerization.Polymerization is followed by fluorescence enhancement due to theincorporation of a fluorescent reporter into microtubules aspolymerization occurs. The standard assay tubulin generates apolymerization curve representing the three phases of microtubuleformation, namely nucleation, growth, and steady state equilibrium.Compounds that interact with tubulin will often alter one or more of thecharacteristic phases of polymerization. For example, the anti-mitoticdrug paclitaxel eliminates the nucleation phase and enhances the Vmax ofthe growth phase. Similarly, the microtubule destabilizing drug,vinblastine (also antimitotic) causes a decrease in Vmax and a reductionin final polymer mass. Thus, one application of this assay is theidentification of novel anti-mitotics.

The direct effects of the test compounds on tubulin polymerization wereinvestigated using the abovementioned Tubulin polymerization assay kit(Cytoskeleton, Cat. #BK011P), as indicated by the manufacturer protocol.Briefly, bovine brain tubulin (400 μg/sample) in the presence of either0.5% DMSO treated (control), or increasing concentrations of each testcompounds was incubated in PEM buffer [80 mm PIPES, 1 mm EGTA, 1 mmMgCl₂ (pH 6.8)] containing 1.0 mm GTP (G-PEM) and 15% glycerol, at 37 C.All samples (wells) contained 15% glycerol. The degree of polymerizationover time was measured in a spectrophotometer (Biotek synergy HT platereader) at 350 nm. All time points were plotted and analyzed usingGraphPad Prism 6.0 software.

The IC50 values were determined by performing non-linear regressionanalysis fitting velocities and the logarithm of inhibitorconcentrations to a sigmoidal dose response with a variable slope modelusing the GraphPad Prism 6.0 software.

Cell Viability Assay in Solid Tumors Cell Lines

Human cancer cell lines (lung, ovarian, breast pancreatic andmesothelioma) were purchased from the ATCC. The cell lines were culturedin RPMI 1640 (Life Technologies, Carlsbad, Calif.) supplemented with 10%fetal bovine serum (FBS) and antibiotics. 2000 cells were seeded in 96well costar plate one day before treatment with test compounds, Olaparib(Selleck Chemicals), Imatnib Mesylate (Selleck Chemicals) or ponatinibat different concentrations for 72 hours, with vehicle (DMSO) ascontrols. At the end of treatment, cell proliferation was determined byan intracellular adenosine triphosphate monitoring system (Cell-TiterGlo-Promega). Cell lines tested included A549 cells=Human lungadenocarcinoma; OVCAR-8 Cells=Human Ovarian adenocarcinoma; MDA-MB-436Cells=Human Breast adenocarcinoma cell line with BRCA1-mutation.

Inhibitory activity was evaluated comparing treated versus control datausing the GraphPad Prism 6.0 software. The dose inhibiting 50% (IC50) ofcell viability was calculated using non-linear regression curve. Resultsshow the mean IC50 value from three different experiments.

Data obtained from these assays for compounds of the invention areprovided in FIG. 1A-FIG. 1O.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A compound, or a salt or a hydrate or a solvatethereof, having a structure according to formula (I):

wherein T has a structure which is

wherein

represents a covalent bond to the methylene group in formula (I) and

represents a covalent bond to the U ring in formula (I) wherein formula(C)

wherein

represents a covalent bond to the T ring in formula (I) and

represents a covalent bond to —NH—Y—Z—R¹ in formula (I), has a structurewhich is

wherein Y is C(O) or S(O)₂; Z is —O— or —CH₂— or —NH— or —N(CH₂R⁷)—wherein R⁷ is hydrogen or substituted or unsubstituted C₁ or C₂ or C₃ orC₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl; R¹ is unsubstituted C₂ orC₁ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl or hydrogen orsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₅ or C₉ or C₁₀alkyl or substituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆or C₇ or C₈ or C₉ or C₁₀ heteroalkyl or substituted or unsubstitutedaryl or substituted or unsubstituted arylalkyl or substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl; R² is hydrogen or halogen or substituted orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl; R³ is halogen or hydrogen or substituted or unsubstituted C₁ orC₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl or substitutedor unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ orC₁₀ alkoxy; R⁴ is hydrogen or halogen or substituted or unsubstituted C₁or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl orsubstituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ orC₈ or C₉ or C₁₀ alkoxy; R⁵ is hydrogen or halogen or substituted orunsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀alkyl; and R⁶ is hydrogen or halogen or substituted or unsubstituted C₁or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ or C₁₀ alkyl.
 2. Thecompound of claim 1, or a salt or a hydrate or a solvate thereof, havinga structure which is

wherein R² is hydrogen or F or Cl or unsubstituted C₁ or C₂ or C₃ alkyl;R³ is hydrogen or F or Cl or unsubstituted C₁ or C₂ or C₃ or alkyl orsubstituted or unsubstituted C₁ or C₂ or C₃ alkoxy; and R⁴ is hydrogenor F or Cl or unsubstituted C₁ or C₂ or C₃ or alkyl or substituted orunsubstituted C₁ or C₂ or C₃ alkoxy.
 3. The compound of claim 1, or asalt or a hydrate or a solvate thereof, having a structure which is


4. The compound of claim 1, or a salt or a hydrate or a solvate thereof,having a structure which is


5. The compound of claim 1, or a salt or a hydrate or a solvate thereof,having a structure which is


6. The compound of claim 1, or a salt or a hydrate or a solvate thereof,having a structure which is


7. The compound of claim 1, or a salt or a hydrate or a solvate thereof,having a structure which is


8. The compound of claim 1, or a salt or a hydrate or a solvate thereof,having a structure which is


9. The compound of claim 1, or a salt or a hydrate or a solvate thereof,having a structure which is


10. The compound of claim 1, or a salt or a hydrate or a solvatethereof, having a structure which is


11. The compound of claim 1, or a salt or a hydrate or a solvatethereof, having a structure which is


12. The compound of claim 1, or a salt or a hydrate or a solvatethereof, having a structure which is


13. The compound of claims 1-12, or a salt or a hydrate or a solvatethereof, wherein R² is H and R³ is H; or R² is F and R³ is H; or R² is Hand R³ is F; or R² is F and R³ is F; or R² is H and R³ is Cl; or R² is Fand R³ is Cl; or R² is H and R³ is —OCH₃; or R² is H and R³ is —OCHF₂;or R² is H and R³ is —OCF₃; or R² is H and R³ is —CH₃; or R² is H and R³is —OCH₂CH₃; or R² is H and R³ is —CF₃.
 14. The compound of claims 1-13,or a salt or a hydrate or a solvate thereof, wherein R¹ is substitutedor unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ or C₆ or C₇ or C₈ or C₉ orC₁₀ alkyl or substituted or unsubstituted C₁ or C₂ or C₃ or C₄ or C₅ orC₆ or C₇ or C₈ or C₉ or C₁₀ heteroalkyl or substituted or unsubstitutedaryl or substituted or unsubstituted arylalkyl or substituted orunsubstituted cycloalkyl or substituted or unsubstitutedheterocycloalkyl.
 15. The compound of claims 1-14, or a salt or ahydrate or a solvate thereof, wherein R¹ is methyl.
 16. The compound ofclaims 1-14, or a salt or a hydrate or a solvate thereof, wherein R¹ isethyl.
 17. The compound of claims 1-14, or a salt or a hydrate or asolvate thereof, wherein R¹ is —(CH₂)_(m)OR^(1a), wherein R^(1a) issubstituted or unsubstituted C₁ or C₂ or C₃ alkyl, and m is 2 or
 3. 18.The compound of claims 1-14, or a salt or a hydrate or a solvatethereof, wherein R¹ is —(CH₂)₂OCH₃.
 19. The compound of claims 1-14, ora salt or a hydrate or a solvate thereof, wherein R¹ is propyl or—CH₂CH₂F or —CH₂CHF₂ or —CH₂CF₃ or —CH(CH₃)₂ or —CH(CH₃)(CH₂CH₃) orcyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl or oxetanyl ortetrahydropyranyl or azetidinyl or methylazetidinyl or piperidinyl ormethylpiperidinyl or phenyl or benzyl or —(CH₂)_(m)NR^(1b)R^(1c),wherein R^(1b) is hydrogen or substituted or unsubstituted C₁ or C₂ orC₃ alkyl and R^(1c) is hydrogen or substituted or unsubstituted C₁ or C₂or C₃ alkyl and m is 1 or 2 or 3, with the proviso that R^(1b) andR^(1c) can optionally be joined to form a 4-7 membered ring.
 20. Thecompound of claims 1-13, or a salt or a hydrate or a solvate thereof,wherein R¹ is —(CH₂)₂OCH₃, R² is H, and R³ is H; or R¹ is —(CH₂)₂OCH₃,R² is H, and R³ is F; or R¹ is methyl, R² is F, and R³ is F; or R¹ isethyl, R² is F, and R³ is F; or R¹ is —(CH₂)₂OCH₃, R² is F, and R³ is F;or R¹ is methyl; R² is H; and R³ is —CH₃; or R¹ is ethyl; R² is H; andR³ is —CH₃; or R¹ is —(CH₂)₂OCH₃, R² is H; and R³ is —CH₃; or R¹ ismethyl; R² is H; and R³ is —OCH₃; or R¹ is ethyl; R² is H; and R³ is—OCH₃; or R¹ is —(CH₂)₂OCH₃, R² is H; and R³ is —OCH₃; or R¹ is methyl;R² is H; and R³ is —OCHF₂; or R¹ is ethyl; R² is H; and R³ is —OCHF₂; orR¹ is —(CH₂)₂OCH₃, R² is H; and R³ is —OCHF₂; or R¹ is methyl; R² is H;and R³ is —OCH₂CH₃; or R¹ is ethyl; R² is H; and R³ is —OCH₂CH₃; or R¹is —(CH₂)₂OCH₃, R² is H; and R³ is —OCH₂CH₃.
 21. The compound of claims1-12, or a salt or a hydrate or a solvate thereof, wherein R¹ is methyl;R² is H; and R³ is F.
 22. The compound of claims 1-12, or a salt or ahydrate or a solvate thereof, wherein R¹ is ethyl; R² is H; and R³ is F.23. A pharmaceutical formulation comprising: a) the compound, or a saltor a hydrate or a solvate thereof, of claims 1-22; and b) apharmaceutically acceptable excipient.
 24. The pharmaceuticalformulation of claim 23, wherein the pharmaceutical formulation is aunit dosage form.
 25. The pharmaceutical formulation of claim 23 or 24,wherein the salt of the compound is a pharmaceutically acceptable salt.26. A method of inhibiting PARP1 and/or PARP2 and/or tubulin,comprising: contacting said PARP1 and/or PARP2 and/or tubulin with aneffective amount of the compound of claims 1-22, thereby inhibiting saidPARP1 and/or PARP2 and/or tubulin.
 27. A method of treating a disease inan animal, comprising: administering to an animal in need of treatmentthereof a therapeutically effective amount of the compound of claims1-22, thereby treating the disease.
 28. The method of claim 27, whereinthe disease is cancer.
 29. The method of claim 27 or 28, wherein theanimal is a human.
 30. A use of the compound of a preceding claim in themanufacture of a medicament for the treatment of cancer.